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human MutSα•heteroduplex complex image courtesy of Lorena Beese Mechanisms in E. coli & human mismatch repair Paul Modrich HHMI & Dept Biochemistry Duke University

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Page 1: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI

human MutSα•heteroduplex compleximage courtesy of Lorena Beese

Mechanisms in E. coli & humanmismatch repair

Paul ModrichHHMI & Dept Biochemistry

Duke University

Page 2: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 3: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 4: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 5: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 6: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 7: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 8: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 9: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 10: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 11: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI

LA Aaltonen et al (1993), Y Ionov et al (1993)

Microsatellite instability in tumor cells

Frequent mutations in (CA)n and (A)n microsatelliterepeat sequences are a characteristic of:

• tumors in Lynch syndrome patients(colon, endometrial, ovarian & gastric cancers;accounts for ≈ 5% of total colon cancer burden)

• ≈ 15% of Lynch-like sporadic cancers

Such mutations are also common in E. coli mismatchrepair mutants (Levinson and Gutman (1987))

Page 12: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI

Cell lines derived from tumors with microsatellite instabilityare deficient in MutLα or MutSα

Tumor cell line Microsatellite instability

3’ G-T heteroduplexrepair (fmol)

Defect

HeLa (cervix) No 9 --

SW480 (colon) No 13 --

Vaco 410 (colon) No 7.4 --

LoVo (colon) Yes < 0.3 MutSα

HCT-15 (colon) Yes < 0.3 MutSα

HEC-59 (endometrial) Yes < 0.3 MutSα

HCT 116 (colon) Yes < 0.3 MutLα

Vaco 481 (colon) Yes < 0.3 MutLα

RKO (colon)* Yes < 0.3 MutLα

Vaco 5 (colon)* Yes 0.4 MutLα

Vaco 6 (colon)* Yes < 0.3 MutLα

AN3CA (endometrial)* Yes < 0.3 MutLα

R Parsons et al (1993), J Drummond et al (1995), G-M Li et al (1995), ML Veigl et al (1998)

*sporadic cancers with MLH1 epigenetically silenced

Page 13: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 14: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 15: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 16: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 17: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 18: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 19: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 20: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI
Page 21: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI

Do 5’- and 3’-termini at the fork function as default strand signals to direct mismatch repair?

Graphic courtesy of Peter Burgers

Page 22: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI

Current and some former laboratory colleaguesDuke, October 12, 2015

Page 23: Mechanisms in E. coli & human mismatch repairhuman MutSα•heteroduplex complex. image courtesy of Lorena Beese. Mechanisms in . E. coli & human. mismatch repair. Paul Modrich. HHMI

In order of appearance

Gail HermanA-Lien LuShin-San (Michael) SuKatherine WelshRobert LahueDeani CooperBeverly YasharKarin AuMichelle GrilleyJude HolmesWoei-horng FangLeroy WorthDwayne AllenJohn TaylorGuo-Min LiMiyuki YamaguchiMarc PrudhommeMatthew LongleyJane SmithVivian DaoWendy Bedale

James DrummondElisabeth PenlandCelia BaitingerSusan LittmanDawn ChandrasekharAndrew PierceDerek DuckettJochen GenschelLeonard BlackwellDiana MartikMaynard BronsteinGreg RunyonYizhong ShaRochelle BazemoreKeith BjornsonShuntai WangVickers BurdettKent ChristiansenClaudia SpampinatoSihong ChenNicoleta Constantin

Leonid DzantievRavi IyerAnna PluciennikSally YorkLored AsllaniFarid KadyrovYanan FangOlga LukianovaYiyong LiuHongbing ShaoZingdong ZhangShanen Sherrer

Laboratory Colleagues CollaboratorsMatthew MeselsonJosef JiricnyJack GriffithWilliam ThillyBert VogelsteinHenry FriedmanAziz SancarDavid LilleySanford MarkowitzMartina VeiglDavid SedwickLorena BeeseSandra BignerSusan LovettPeter BurgersMike O’DonnellDorothy ErieKaren Vasquez


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