Kara A. Bernstein

Abstract: Protein acetylation is mediated by histone acetyltransferases (HATs) and deacetylases (HDACs), which influence chromatin dynamics, protein turnover and the DNA damage response. ATM and ATR mediate DNA damage checkpoints by sensing double-strand breaks and single-strand-DNA-RFA nucleofilaments, respectively. However, it is unclear how acetylation modulates the DNA damage response. Here we show that HDAC inhibition/ablation specifically counteracts yeast Mec1 (orthologue of human ATR) activation, double-strand-break processing and single-strand-DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CtIP) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3, and one HAT, Gcn5, have key roles in these processes. We also find that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of hda1 and rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor, also causes Sae2 degradation. We propose that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy.

TL;DR: It is proposed that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy, and it is found that HDAC inhibition triggers Sae2 degradation by promoting Autophagy that affects the DNA damage sensitivity of hda 1 and rpd3 mutants.

TL;DR: RecQ function in these different processing steps has important implications for its role in repair of double-strand breaks that occur during DNA replication and meiosis, as well as at specific genomic loci such as telomeres.

TL;DR: Evidence is provided for these primary mutations in RAD51C and RAD51D in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance underpins the need for early delivery of PARPi therapy and for combination strategies.

TL;DR: 12 additional protein components are characterized, including five small-ribosomal-subunit proteins and seven other proteins found to be bona fide SSU processome proteins that may be analogous to the primary or secondary RNA binding proteins first described in bacterial in vitro ribosome assembly maps.