Convergence of SIRT1 and ATR signaling to modulate replication origin dormancy

Author:

Thakur Bhushan L1,Baris Adrian M1,Fu Haiqing1,Redon Christophe E1,Pongor Lorinc S1,Mosavarpour Sara1,Gross Jacob M1,Jang Sang-Min1,Sebastian Robin1,Utani Koichi1,Jenkins Lisa M2,Indig Fred E3,Aladjem Mirit I1ORCID

Affiliation:

1. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA

2. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA

3. Confocal Imaging Facility, National Institute on Aging, NIH, Baltimore, MD 21224, USA

Abstract

Abstract During routine genome duplication, many potential replication origins remain inactive or ‘dormant’. Such origin dormancy is achieved, in part, by an interaction with the metabolic sensor SIRT1 deacetylase. We report here that dormant origins are a group of consistent, pre-determined genomic sequences that are distinguished from baseline (i.e. ordinarily active) origins by their preferential association with two phospho-isoforms of the helicase component MCM2. During normal unperturbed cell growth, baseline origins, but not dormant origins, associate with a form of MCM2 that is phosphorylated by DBF4-dependent kinase (DDK) on serine 139 (pS139-MCM2). This association facilitates the initiation of DNA replication from baseline origins. Concomitantly, SIRT1 inhibits Ataxia Telangiectasia and Rad3-related (ATR)-kinase-mediated phosphorylation of MCM2 on serine 108 (pS108-MCM2) by deacetylating the ATR-interacting protein DNA topoisomerase II binding protein 1 (TOPBP1), thereby preventing ATR recruitment to chromatin. In cells devoid of SIRT1 activity, or challenged by replication stress, this inhibition is circumvented, enabling ATR-mediated S108-MCM2 phosphorylation. In turn, pS108-MCM2 enables DDK-mediated phosphorylation on S139-MCM2 and facilitates replication initiation at dormant origins. These observations suggest that replication origin dormancy and activation are regulated by distinct post-translational MCM modifications that reflect a balance between SIRT1 activity and ATR signaling.

Funder

National Cancer Institute

National Institute on Aging

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference67 articles.

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