TRIP13 regulates DNA repair pathway choice through REV7 conformational change

被引：115

作者：

Clairmont, Connor S. ^{[1
]}

Sarangi, Prabha ^{[1
]}

Ponnienselvan, Karthikeyan ^{[1
]}

Galli, Lucas D. ^{[1
]}

Csete, Isabelle ^{[1
]}

Moreau, Lisa ^{[1
]}

Adelmant, Guillaume ^{[2
,3
,4
,5
,6
]}

Chowdhury, Dipanjan ^{[1
]}

Marto, Jarrod A. ^{[2
,3
,4
,5
,6
]}

D'Andrea, Alan D. ^{[1
,7
]}

机构：

[1] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[6] Harvard Med Sch, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02115 USA

来源：

NATURE CELL BIOLOGY | 2020年 / 22卷 / 01期

基金：

美国国家卫生研究院;

关键词：

SPINDLE CHECKPOINT PROTEIN; MUTATIONAL SIGNATURES; STRUCTURAL BASIS; POLYMERASE-ZETA; HORMA DOMAIN; COMPLEX; DAMAGE; BREAKS; TUMOR; INACTIVATION;

D O I：

10.1038/s41556-019-0442-y

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

DNA double-strand breaks (DSBs) are repaired through homology-directed repair (HDR) or non-homologous end joining (NHEJ). BRCA1/2-deficient cancer cells cannot perform HDR, conferring sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). However, concomitant loss of the pro-NHEJ factors 53BP1, RIF1, REV7-Shieldin (SHLD1-3) or CST-DNA polymerase alpha (Pol-alpha) in BRCA1-deficient cells restores HDR and PARPi resistance. Here, we identify the TRIP13 ATPase as a negative regulator of REV7. We show that REV7 exists in active 'closed' and inactive 'open' conformations, and TRIP13 catalyses the inactivating conformational change, thereby dissociating REV7-Shieldin to promote HDR. TRIP13 similarly disassembles the REV7-REV3 translesion synthesis (TLS) complex, a component of the Fanconi anaemia pathway, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair. Importantly, TRIP13 overexpression is common in BRCA1-deficient cancers, confers PARPi resistance and correlates with poor prognosis. Thus, TRIP13 emerges as an important regulator of DNA repair pathway choice-promoting HDR, while suppressing NHEJ and TLS.

引用

页码：87 / +

页数：23

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