PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice | Zendy

Ayako L. Mochizuki | Zendy; Ami Katanaya | Zendy; Eri Hayashi | Zendy; Mihoko Hosokawa | Zendy; Emiko Moribe | Zendy; Akira Motegi | Zendy; Masamichi Ishiai | Zendy; Minoru Takata | Zendy; Gen Kondoh | Zendy; Hitomi Watanabe | Zendy; Norio Nakatsuji | Zendy; Shinichiro Chuma | Zendy

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PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice

Author(s) -

Ayako L. Mochizuki,

Ami Katanaya,

Eri Hayashi,

Mihoko Hosokawa,

Emiko Moribe,

Akira Motegi,

Masamichi Ishiai,

Minoru Takata,

Gen Kondoh,

Hitomi Watanabe,

Norio Nakatsuji,

Shinichiro Chuma

Publication year - 2017

Publication title -

molecular and cellular biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.14

H-Index - 327

eISSN - 1067-8824

pISSN - 0270-7306

DOI - 10.1128/mcb.00117-17

Subject(s) - biology , control of chromosome duplication , genome instability , dna replication , microbiology and biotechnology , replisome , pre replication complex , genetics , dna re replication , minichromosome maintenance , replication factor c , origin recognition complex , eukaryotic dna replication , licensing factor , dna , dna damage

DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart. Such PARI function is apparently obstructive to replication but is nonetheless physiologically required for chromosome stabilityin vivo andex vivo . Of note,Pari -deficient embryonic stem cells exhibit spontaneous chromosome instability, which is attenuated by differentiation induction, suggesting that pluripotent stem cells have a preferential requirement for PARI that acts against endogenous replication stress. PARI is a latent modulator of stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress in mice.

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