Garabedian MV, Noguchi C, Ziegler MA, Das MM, Singh T, Harper LJ, Leman AR, Khair L, Moser BA, Nakamura TM, Noguchi E

Bromodomain proteins bind acetylated histones to regulate transcription. Emerging evidence suggests that histone acetylation plays an important role in DNA replication and repair, although its precise mechanisms are not well understood. Here we report studies of two double bromodomain-containing proteins, Bdf1 and Bdf2, in fission yeast. Loss of Bdf1 or ...

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Bdf2 led to a reduction in the level of histone H4 acetylation. Both bdf1 and bdf2 cells showed sensitivity to DNA damaging agents including camptothecin that cause replication fork breakage. Consistently, Bdf1 and Bdf2 were important for recovery of broken replication forks and suppression of DNA damage. Surprisingly, deletion of bdf1 or bdf2 partially suppressed sensitivity of various checkpoint mutants including swi1, mrc1, cds1, crb2, chk1, and rad3, to hydroxyurea, a compound that stalls replication forks and activates the Cds1-dependent S-phase checkpoint. This suppression was not due to reactivation of Cds1. Instead, we found that bdf2 deletion alleviates DNA damage accumulation caused by defects in the DNA replication checkpoint. We also show that hydroxyurea sensitivity of mrc1 and vswi1 was suppressed by mutations in histone H4 acetyltransferase subunits or histone H4. These results suggest that the double bromodomain-containing proteins modulate chromatin structure to coordinate DNA replication and S-phase stress response.

Date: Nov. 17, 2011

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