Abstract:
:Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4 As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation.
journal_name
Proc Natl Acad Sci U S Aauthors
Wang R,Lenoir WF,Wang C,Su D,McLaughlin M,Hu Q,Shen X,Tian Y,Klages-Mundt N,Lynn E,Wood RD,Chen J,Hart T,Li Ldoi
10.1073/pnas.2008821117subject
Has Abstractpub_date
2020-12-29 00:00:00pages
33436-33445issue
52eissn
0027-8424issn
1091-6490pii
2008821117journal_volume
117pub_type
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