Journal
MOLECULAR CELL
Volume 58, Issue 2, Pages 323-338Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.02.031
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Funding
- NCI NIH HHS [P30 CA008748] Funding Source: Medline
- NIGMS NIH HHS [GM110385, GM057691, R01 GM057691, GM094972, GM084244, R01 GM084244, R21 GM110385, R01 GM094972] Funding Source: Medline
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Excess dormant origins bound by the minichromosome maintenance (MCM) replicative helicase complex play a critical role in preventing replication stress, chromosome instability, and tumorigenesis. In response to DNA damage, replicating cells must coordinate DNA repair and dormant origin firing to ensure complete and timely replication of the genome; how cells regulate this process remains elusive. Herein, we identify a member of the Fanconi anemia (FA) DNA repair pathway, FANCI, as a key effector of dormant origin firing in response to replication stress. Cells lacking FANCI have reduced number of origins, increased inter-origin distances, and slowed proliferation rates. Intriguingly, ATR-ediated FANCI phosphorylation inhibits dormant origin firing while promoting replication fork restart/DNA repair. Using super-resolution microscopy, we show that FANCI co-localizes with MCM-bound chromatin in response to replication stress. These data reveal a unique role for FANCI as a modulator of dormant origin firing and link timely genome replication to DNA repair.
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