>PPIA|NM_021130|3'UTR
   1 GTTTGACTTGTGTTTTATCTTAACCACCAGATCATTCCTTCTGTAGCTCAGGAGAGCACCCCTCCACCCCATTTGCTCGC
  81 AGTATCCTAGAATCTTTGTGCTCTCGCTGCAGTTCCCTTTGGGTTCCATGTTTTCCTTGTTCCCTCCCATGCCTAGCTGG
 161 ATTGCAGAGTTAAGTTTATGATTATGAAATAAAAACTAAATAACAATTGTCCTCGTTTGAGTTAAGAGTGTTGATGTAGG
 241 CTTTATTTTAAGCAGTAATGGGTTACTTCTGAAACATCACTTGTTTGCTTAATTCTACACAGTACTTAGATTTTTTTTAC
 321 TTTCCAGTCCCAGGAAGTGTCAATGTTTGTTGAGTGGAATATTGAAAATGTAGGCAGCAACTGGGCATGGTGGCTCACTG
 401 TCTGTAATGTATTACCTGAGGCAGAAGACCACCTGAGGGTAGGAGTCAAGATCAGCCTGGGCAACATAGTGAGACGCTGT
 481 CTCTACAAAAAATAATTAGCCTGGCCTGGTGGTGCATGCCTAGTCCTAGCTGATCTGGAGGCTGACGTGGGAGGATTGCT
 561 TGAGCCTAGAGTGAGCTATTATCATGCCACTGTACAGCCTGGGTGTTCACAGATCTTGTGTCTCAAAGGTAGGCAGAGGC
 641 AGGAAAAGCAAGGAGCCAGAATTAAGAGGTTGGGTCAGTCTGCAGTGAGTTCATGCATTTAGAGGTGTTCTTCAAGATGA
 721 CTAATGTCAAAAATTGAGACATCTGTTGCGGTTTTTTTTTTTTTTTTTTCCCCTGGAATGCAGTGGCGTGATCTCAGCTC
 801 ACTGCAGCCTCCGCCTCCTGGGTTCAAGTGATTCTAGTGCCTCAGCCTCCTGAGTAGCTGGGATAATGGGCGTGTGCCAC
 881 CATGCCCAGCTAATTTTTGTATTTTTAGTATAGATGGGGTTTCATCATTTTGACCAGGCTGGTCTCAAACTCTTGACCTC
 961 AGCTGATGCGCCTGCCTTGGCCTCCCAAACTGCTGAGATTACAGATGTGAGCCACCGCACCCTACCTCATTTTCTGTAAC
1041 AAAGCTAAGCTTGAACACTGTTGATGTTCTTGAGGGAAGCATATTGGGCTTTAGGCTGTAGGTCAAGTTTATACATCTTA
1121 ATTATGGTGGAATTCCTATGTAGAGTCTAAAAAGCCAGGTACTTGGTGCTACAGTCAGTCTCCCTGCAGAGGGTTAAGGC
1201 GCAGACTACCTGCAGTGAGGAGGTACTGCTTGTAGCATATAGAGCCTCTCCCTAGCTTTGGTTATGGAGGCTTTGAGGTT
1281 TTGCAAACCTGACCAATTTAAGCCATAAGATCTGGTCAAAGGGATACCCTTCCCACTAAGGACTTGGTTTCTCAGGAAAT
1361 TATATGTACAGTGCTTGCTGGCAGTTAGATGTCAGGACAATCTAAGCTGAGAAAACCCCTTCTCTGCCCACCTTAACAGA
1441 CCTCTAGGGTTCTTAACCCAGCAATCAAGTTTGCCTATCCTAGAGGTGGCGGATTTGATCATTTGGTGTGTTGGGCAATT
1521 TTTGTTTTACTGTCTGGTTCCTTCTGCGTGAATTACCACCACCACCACTTGTGCATCTCAGTCTTGTGTGTTGTCTGGTT
1601 ACGTATTCCCTGGGTGATACCATTCAATGTCTTAATGTACTTGTGGCTCAGACCTGAGTGCAAGGTGGAAATAAACATCA
1681 AACATCTTTTCATTATCCCTA

ID	Duplex structure	Position	Score	MFE
1	miRNA 3' cuucuuCUUAGUAGUCCUCc 5' | | | ||||||| Target 5' ccttctGTAGC-TCAGGAGa 3'	37 - 55	141.00	-9.60
2	miRNA 3' cuUCUU---CUUAGUAGUCCUcc 5' ||:| |: |: |||||| Target 5' taAGGACTTGGTTTCTCAGGAaa 3'	1337 - 1359	130.00	-8.70
3	miRNA 3' cuUCUUC--UUAGUAGUCCUcc 5' :| || |: ::|||||| Target 5' ctGGCAGTTAGATGTCAGGAca 3'	1378 - 1399	128.00	-8.30

Mutant ID	Mutant Position	Mutant Source
COSN30522825	6	COSMIC
COSN30535771	41	COSMIC
COSN30159843	50	COSMIC
COSN19632944	64	COSMIC
COSN28509905	102	COSMIC
COSN20104206	228	COSMIC
COSN27786474	555	COSMIC
COSN20303380	582	COSMIC
COSN23248090	584	COSMIC
COSN20104212	754	COSMIC
COSN27291439	754	COSMIC
COSN27366407	754	COSMIC
COSN15350273	755	COSMIC
COSN8023415	756	COSMIC
COSN22499583	757	COSMIC
COSN20104213	770	COSMIC
COSN20562830	771	COSMIC
COSN27518377	774	COSMIC
COSN9990068	933	COSMIC
COSN8023416	1222	COSMIC
COSN24626913	1285	COSMIC
COSN27937483	1339	COSMIC
COSN20104214	1415	COSMIC
COSN25819019	1510	COSMIC

Mutant ID	Mutant Position	Mutant Source
rs1215991146	3	dbSNP
rs756729147	8	dbSNP
rs778610995	13	dbSNP
rs745573436	14	dbSNP
rs1255345032	15	dbSNP
rs771867229	18	dbSNP
rs913839962	20	dbSNP
rs1189315135	21	dbSNP
rs1368696162	22	dbSNP
rs1438632084	23	dbSNP
rs1156444464	28	dbSNP
rs561066382	31	dbSNP
rs1419742374	32	dbSNP
rs746822337	33	dbSNP
rs768649599	34	dbSNP
rs1161325011	36	dbSNP
rs761973517	37	dbSNP
rs886320707	39	dbSNP
rs1394685151	41	dbSNP
rs765301920	44	dbSNP
rs773456224	47	dbSNP
rs1043373937	48	dbSNP
rs1239764860	51	dbSNP
rs1004815182	52	dbSNP
rs763136493	53	dbSNP
rs903493344	55	dbSNP
rs996567587	60	dbSNP
rs1049447386	61	dbSNP
rs17860084	62	dbSNP
rs11547711	63	dbSNP
rs1213851100	64	dbSNP
rs11266776	66	dbSNP
rs1266550888	67	dbSNP
rs1211135693	77	dbSNP
rs1008843048	79	dbSNP
rs549994697	80	dbSNP
rs961971571	83	dbSNP
rs9961	86	dbSNP
rs1200608074	87	dbSNP
rs1029114773	89	dbSNP
rs995720018	91	dbSNP
rs1302275401	95	dbSNP
rs1381825535	98	dbSNP
rs1026996085	101	dbSNP
rs987840716	102	dbSNP
rs1381488144	105	dbSNP
rs571726170	106	dbSNP
rs1031011654	107	dbSNP
rs1377654230	111	dbSNP
rs1192026542	112	dbSNP
rs1447221260	118	dbSNP
rs980079962	119	dbSNP
rs1249494534	121	dbSNP
rs17860085	122	dbSNP
rs1384411428	126	dbSNP
rs879489327	129	dbSNP
rs1278601948	133	dbSNP
rs960142898	135	dbSNP
rs1347260948	136	dbSNP
rs1256595531	137	dbSNP
rs1227962560	145	dbSNP
rs547761897	149	dbSNP
rs913694610	150	dbSNP
rs1439915144	151	dbSNP
rs1339598188	152	dbSNP
rs1332148321	166	dbSNP
rs1416032911	168	dbSNP
rs8177829	172	dbSNP
rs1402306752	178	dbSNP
rs1166866454	197	dbSNP
rs945300886	199	dbSNP
rs1427259052	202	dbSNP
rs948252420	204	dbSNP
rs1043597514	207	dbSNP
rs924969682	210	dbSNP
rs1450505782	213	dbSNP
rs1237224764	215	dbSNP
rs566320533	216	dbSNP
rs1444578162	219	dbSNP
rs1257465790	224	dbSNP
rs17860086	225	dbSNP
rs386544857	225	dbSNP
rs8177830	225	dbSNP
rs1340112415	227	dbSNP
rs927084957	234	dbSNP
rs1049373004	243	dbSNP
rs1379060542	253	dbSNP
rs1229360866	256	dbSNP
rs938452146	263	dbSNP
rs1237916930	275	dbSNP
rs1278419093	279	dbSNP
rs1449934246	281	dbSNP
rs1356506938	287	dbSNP
rs1307308697	290	dbSNP
rs1057172010	293	dbSNP
rs1371819244	298	dbSNP
rs907551542	301	dbSNP
rs940583222	302	dbSNP
rs1287306236	309	dbSNP
rs1413542989	310	dbSNP
rs17860087	311	dbSNP
rs397704534	311	dbSNP
rs397816218	311	dbSNP
rs1369598395	312	dbSNP
rs1182025289	313	dbSNP
rs1482131744	315	dbSNP
rs1253979981	320	dbSNP
rs1206152160	326	dbSNP
rs1467373338	330	dbSNP
rs1213494971	332	dbSNP
rs890905522	333	dbSNP
rs191837591	337	dbSNP
rs1037648992	344	dbSNP
rs1356765539	344	dbSNP
rs1287676181	350	dbSNP
rs898988309	352	dbSNP
rs111735829	363	dbSNP
rs1050256694	366	dbSNP
rs776433516	371	dbSNP
rs1037609335	381	dbSNP
rs1363300481	382	dbSNP
rs374908469	385	dbSNP
rs1473172177	388	dbSNP
rs897287659	392	dbSNP
rs890504644	394	dbSNP
rs139105425	395	dbSNP
rs1414815085	398	dbSNP
rs144790995	401	dbSNP
rs1477723953	405	dbSNP
rs1245254518	409	dbSNP
rs1223992689	411	dbSNP
rs1452000934	416	dbSNP
rs1027263268	423	dbSNP
rs1031398871	430	dbSNP
rs1331215047	441	dbSNP
rs906100303	442	dbSNP
rs1218181648	450	dbSNP
rs1460689190	452	dbSNP
rs1276281024	454	dbSNP
rs1001568402	458	dbSNP
rs1331749511	459	dbSNP
rs1402250932	462	dbSNP
rs1320368078	464	dbSNP
rs11547708	469	dbSNP
rs1035691758	476	dbSNP
rs960400112	477	dbSNP
rs988875659	479	dbSNP
rs1340477771	480	dbSNP
rs1011101257	482	dbSNP
rs1246365464	484	dbSNP
rs143350466	487	dbSNP
rs1193147082	488	dbSNP
rs1454830980	496	dbSNP
rs969525332	499	dbSNP
rs980871301	500	dbSNP
rs1466064998	502	dbSNP
rs533067408	506	dbSNP
rs928149740	528	dbSNP
rs1309938173	533	dbSNP
rs1218919862	535	dbSNP
rs1021218140	536	dbSNP
rs1219286974	545	dbSNP
rs960033981	546	dbSNP
rs1294904057	547	dbSNP
rs17860088	548	dbSNP
rs1367735677	550	dbSNP
rs17860089	552	dbSNP
rs1447862087	565	dbSNP
rs541358110	570	dbSNP
rs1443028026	575	dbSNP
rs1178399101	576	dbSNP
rs1037618214	579	dbSNP
rs920469185	580	dbSNP
rs17860090	581	dbSNP
rs759041932	582	dbSNP
rs985569558	583	dbSNP
rs890315706	584	dbSNP
rs912191920	593	dbSNP
rs943793404	596	dbSNP
rs1210253920	598	dbSNP
rs753476943	599	dbSNP
rs754803033	602	dbSNP
rs1402847119	603	dbSNP
rs931498228	604	dbSNP
rs1397757417	606	dbSNP
rs764864527	610	dbSNP
rs765003104	616	dbSNP
rs1354336083	618	dbSNP
rs1010901698	623	dbSNP
rs11984372	626	dbSNP
rs574645132	635	dbSNP
rs1279708604	637	dbSNP
rs141838679	640	dbSNP
rs758334118	650	dbSNP
rs895785244	653	dbSNP
rs781206974	666	dbSNP
rs1225728868	670	dbSNP
rs1020393981	671	dbSNP
rs570848571	673	dbSNP
rs1415934042	685	dbSNP
rs181557589	688	dbSNP
rs767884699	695	dbSNP
rs979270449	718	dbSNP
rs1482462539	724	dbSNP
rs560929101	726	dbSNP
rs1346285458	736	dbSNP
rs953968318	738	dbSNP
rs1480788565	745	dbSNP
rs531716578	750	dbSNP
rs1320269261	751	dbSNP
rs10627827	752	dbSNP
rs1183800492	752	dbSNP
rs1390104503	752	dbSNP
rs1491447187	752	dbSNP
rs35100141	753	dbSNP
rs60471039	754	dbSNP
rs28403980	755	dbSNP
rs989631533	756	dbSNP
rs1426465599	757	dbSNP
rs1214693062	758	dbSNP
rs1329148092	760	dbSNP
rs1266743610	764	dbSNP
rs1230357944	765	dbSNP
rs1336371549	767	dbSNP
rs1300882737	768	dbSNP
rs567298870	768	dbSNP
rs992978462	769	dbSNP
rs117681717	770	dbSNP
rs751464359	770	dbSNP
rs57534886	771	dbSNP
rs1261466756	772	dbSNP
rs1490947685	773	dbSNP
rs1467513174	774	dbSNP
rs1170817458	776	dbSNP
rs985361164	779	dbSNP
rs565514926	780	dbSNP
rs1196320802	783	dbSNP
rs1419796428	787	dbSNP
rs1253234576	788	dbSNP
rs532605623	789	dbSNP
rs547925179	792	dbSNP
rs943741067	795	dbSNP
rs972797081	796	dbSNP
rs918372446	797	dbSNP
rs1464708924	799	dbSNP
rs1266803179	801	dbSNP
rs961791636	802	dbSNP
rs534741910	805	dbSNP
rs1231149911	806	dbSNP
rs920273857	810	dbSNP
rs1381345561	811	dbSNP
rs931864716	812	dbSNP
rs1362709223	813	dbSNP
rs190544520	813	dbSNP
rs879288197	814	dbSNP
rs548241826	818	dbSNP
rs1048595500	821	dbSNP
rs112278761	828	dbSNP
rs905995511	834	dbSNP
rs568616291	836	dbSNP
rs1395352234	843	dbSNP
rs569649936	854	dbSNP
rs1217463937	855	dbSNP
rs944591276	859	dbSNP
rs7784201	868	dbSNP
rs1186207073	869	dbSNP
rs558361547	872	dbSNP
rs1042104903	873	dbSNP
rs1486682608	878	dbSNP
rs1281336689	879	dbSNP
rs1434692731	881	dbSNP
rs1227897366	885	dbSNP
rs892512591	886	dbSNP
rs904657544	893	dbSNP
rs17860093	900	dbSNP
rs570990249	902	dbSNP
rs17860094	904	dbSNP
rs1416109911	922	dbSNP
rs953851611	924	dbSNP
rs1419736572	925	dbSNP
rs905224399	926	dbSNP
rs1007238452	935	dbSNP
rs1002396865	943	dbSNP
rs780290604	945	dbSNP
rs553096208	947	dbSNP
rs1452584224	953	dbSNP
rs965665942	958	dbSNP
rs896643259	963	dbSNP
rs1368446427	965	dbSNP
rs1004342499	967	dbSNP
rs1016183688	969	dbSNP
rs180875884	970	dbSNP
rs749539510	971	dbSNP
rs1388899244	978	dbSNP
rs973170802	984	dbSNP
rs1301813291	996	dbSNP
rs769049572	999	dbSNP
rs983841480	1003	dbSNP
rs149127139	1010	dbSNP
rs539726282	1017	dbSNP
rs1057480991	1018	dbSNP
rs17860095	1019	dbSNP
rs554578118	1034	dbSNP
rs1407453314	1041	dbSNP
rs773905068	1050	dbSNP
rs1041703910	1051	dbSNP
rs1329098217	1051	dbSNP
rs1410902333	1058	dbSNP
rs1390417472	1059	dbSNP
rs913755794	1061	dbSNP
rs904500541	1062	dbSNP
rs1419203883	1065	dbSNP
rs946784589	1067	dbSNP
rs186066318	1070	dbSNP
rs1450823365	1072	dbSNP
rs760202453	1073	dbSNP
rs1489313736	1081	dbSNP
rs1000249398	1083	dbSNP
rs754063499	1086	dbSNP
rs565236966	1089	dbSNP
rs889186398	1093	dbSNP
rs896699724	1098	dbSNP
rs1374816157	1099	dbSNP
rs1004887516	1105	dbSNP
rs190180753	1108	dbSNP
rs1418002212	1111	dbSNP
rs1330900718	1113	dbSNP
rs898690749	1114	dbSNP
rs1019863030	1117	dbSNP
rs1027440800	1120	dbSNP
rs1369857637	1124	dbSNP
rs1463306674	1134	dbSNP
rs1159013447	1139	dbSNP
rs1399055687	1140	dbSNP
rs1410164110	1144	dbSNP
rs1178007686	1149	dbSNP
rs1477854907	1149	dbSNP
rs1324264536	1158	dbSNP
rs1195310653	1160	dbSNP
rs541282758	1163	dbSNP
rs965326147	1171	dbSNP
rs994455541	1173	dbSNP
rs559881826	1177	dbSNP
rs1448162886	1185	dbSNP
rs953023262	1190	dbSNP
rs1318206154	1193	dbSNP
rs1284282396	1196	dbSNP
rs952331234	1201	dbSNP
rs1300424414	1202	dbSNP
rs10256842	1205	dbSNP
rs985775233	1216	dbSNP
rs557595348	1226	dbSNP
rs1320480821	1233	dbSNP
rs1429163958	1238	dbSNP
rs759127720	1240	dbSNP
rs1347447696	1250	dbSNP
rs1223317610	1254	dbSNP
rs958695092	1257	dbSNP
rs1313661382	1266	dbSNP
rs993051427	1279	dbSNP
rs965965519	1281	dbSNP
rs764942391	1284	dbSNP
rs988487824	1285	dbSNP
rs111718472	1287	dbSNP
rs1389251572	1294	dbSNP
rs530445666	1296	dbSNP
rs1041924292	1301	dbSNP
rs1486842236	1303	dbSNP
rs752517191	1305	dbSNP
rs533724784	1306	dbSNP
rs1242597032	1312	dbSNP
rs1208873345	1313	dbSNP
rs1282055329	1316	dbSNP
rs1200384396	1319	dbSNP
rs548898832	1320	dbSNP
rs936027333	1327	dbSNP
rs926669927	1329	dbSNP
rs1364750033	1330	dbSNP
rs1050377534	1336	dbSNP
rs1231116343	1337	dbSNP
rs1289944822	1338	dbSNP
rs889246170	1346	dbSNP
rs938100359	1355	dbSNP
rs563316951	1366	dbSNP
rs143238351	1368	dbSNP
rs1435511008	1368	dbSNP
rs1040891194	1369	dbSNP
rs900971124	1371	dbSNP
rs181164108	1385	dbSNP
rs1474008306	1392	dbSNP
rs1163847287	1393	dbSNP
rs1420164315	1395	dbSNP
rs1181166932	1400	dbSNP
rs6904	1401	dbSNP
rs1466484813	1402	dbSNP
rs1258933337	1403	dbSNP
rs1210961832	1406	dbSNP
rs4205	1412	dbSNP
rs888349701	1412	dbSNP
rs200684634	1415	dbSNP
rs995715092	1418	dbSNP
rs1296960158	1420	dbSNP
rs1460969732	1429	dbSNP
rs1005258001	1430	dbSNP
rs867905174	1439	dbSNP
rs1353662526	1442	dbSNP
rs1295265193	1458	dbSNP
rs1034016060	1460	dbSNP
rs958485989	1467	dbSNP
rs868381565	1476	dbSNP
rs572784239	1485	dbSNP
rs888834647	1486	dbSNP
rs1354828953	1489	dbSNP
rs1018594337	1490	dbSNP
rs966129731	1491	dbSNP
rs1353304769	1492	dbSNP
rs1188093033	1495	dbSNP
rs1471966872	1497	dbSNP
rs1024491128	1506	dbSNP
rs1248008524	1513	dbSNP
rs1178537473	1514	dbSNP
rs756214143	1517	dbSNP
rs1009477937	1519	dbSNP
rs1020865653	1522	dbSNP
rs1213449795	1523	dbSNP
rs14869	1525	dbSNP
rs534697821	1527	dbSNP
rs967927391	1528	dbSNP
rs1275571308	1530	dbSNP
rs1233999730	1533	dbSNP
rs1349901419	1535	dbSNP
rs1305133124	1540	dbSNP
rs1393302103	1541	dbSNP
rs1357518026	1542	dbSNP
rs546503585	1545	dbSNP
rs780053005	1546	dbSNP
rs1413157149	1547	dbSNP
rs1438398232	1548	dbSNP
rs926241723	1549	dbSNP
rs1165502859	1553	dbSNP
rs1361488463	1555	dbSNP
rs760284653	1555	dbSNP
rs1160862254	1559	dbSNP
rs1419367791	1560	dbSNP
rs1318257823	1562	dbSNP
rs1220260995	1566	dbSNP
rs936254271	1573	dbSNP
rs1193448830	1574	dbSNP
rs967940107	1585	dbSNP
rs148317436	1588	dbSNP
rs910508214	1593	dbSNP
rs535399349	1603	dbSNP
rs185715395	1604	dbSNP
rs746881865	1610	dbSNP
rs1438470209	1621	dbSNP
rs992677592	1628	dbSNP
rs1326504154	1634	dbSNP
rs1434206096	1637	dbSNP
rs1382682122	1649	dbSNP
rs1238698461	1651	dbSNP
rs897888855	1655	dbSNP
rs1376767572	1658	dbSNP
rs917913475	1659	dbSNP
rs556846068	1666	dbSNP
rs1452964053	1674	dbSNP
rs1397206476	1675	dbSNP
rs929821514	1680	dbSNP
rs1447000678	1685	dbSNP
rs140505462	1691	dbSNP

- mBio, 2013

UNLABELLED: The question of how HIV-1 interfaces with cellular microRNA (miRNA) biogenesis and effector mechanisms has been highly controversial. Here, we first used deep sequencing of small RNAs present in two different infected cell lines (TZM-bl and C8166) and two types of primary human cells (CD4(+) peripheral blood mononuclear cells [PBMCs] and macrophages) to unequivocally demonstrate that HIV-1 does not encode any viral miRNAs. Perhaps surprisingly, we also observed that infection of T cells by HIV-1 has only a modest effect on the expression of cellular miRNAs at early times after infection. Comprehensive analysis of miRNA binding to the HIV-1 genome using the photoactivatable ribonucleoside-induced cross-linking and immunoprecipitation (PAR-CLIP) technique revealed several binding sites for cellular miRNAs, a subset of which were shown to be capable of mediating miRNA-mediated repression of gene expression. However, the main finding from this analysis is that HIV-1 transcripts are largely refractory to miRNA binding, most probably due to extensive viral RNA secondary structure. Together, these data demonstrate that HIV-1 neither encodes viral miRNAs nor strongly influences cellular miRNA expression, at least early after infection, and imply that HIV-1 transcripts have evolved to avoid inhibition by preexisting cellular miRNAs by adopting extensive RNA secondary structures that occlude most potential miRNA binding sites. IMPORTANCE: MicroRNAs (miRNAs) are a ubiquitous class of small regulatory RNAs that serve as posttranscriptional regulators of gene expression. Previous work has suggested that HIV-1 might subvert the function of the cellular miRNA machinery by expressing viral miRNAs or by dramatically altering the level of cellular miRNA expression. Using very sensitive approaches, we now demonstrate that neither of these ideas is in fact correct. Moreover, HIV-1 transcripts appear to largely avoid regulation by cellular miRNAs by adopting an extensive RNA secondary structure that occludes the ability of cellular miRNAs to interact with viral mRNAs. Together, these data suggest that HIV-1, rather than seeking to control miRNA function in infected cells, has instead evolved a mechanism to become largely invisible to cellular miRNA effector mechanisms.

- Genome research, 2016

DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage-induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA-mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2-miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.

- Neoplasia (New York, N.Y.), 2016

MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable ribonucleoside-enhanced cross-linking immunoprecipitation of the Argonaute protein in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of PCa and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that androgen receptor is the most frequently targeted PCa oncogene and that miR-148a targets the largest number of known PCa drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that, even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in PCa and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.