Abstract：
:Common fragile sites (CFSs) are genomic regions that display gaps and breaks in human metaphase chromosomes under replication stress and are often deleted in cancer cells. We studied an ∼300-bp subregion (Flex1) of human CFS FRA16D in yeast and found that it recapitulates characteristics of CFS fragility in human cells. Flex1 fragility is dependent on the ability of a variable-length AT repeat to form a cruciform structure that stalls replication. Fragility at Flex1 is initiated by structure-specific endonuclease Mus81-Mms4 acting together with the Slx1-4/Rad1-10 complex, whereas Yen1 protects Flex1 against breakage. Sae2 is required for healing of Flex1 after breakage. Our study shows that breakage within a CFS can be initiated by nuclease cleavage at forks stalled at DNA structures. Furthermore, our results suggest that CFSs are not just prone to breakage but also are impaired in their ability to heal, and this deleterious combination accounts for their fragility.
journal_name
Cell Repjournal_title
Cell reportsauthors
Kaushal S,Wollmuth CE,Das K,Hile SE,Regan SB,Barnes RP,Haouzi A,Lee SM,House NCM,Guyumdzhyan M,Eckert KA,Freudenreich CHdoi
10.1016/j.celrep.2019.03.103subject
Has Abstractpub_date
2019-04-23 00:00:00pages
1151-1164.e5issue
4issn
2211-1247pii
S2211-1247(19)30450-4journal_volume
27pub_type
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