Biology subjects

Gomez-Gonzalez, B.

Publications and source records attributed to Gomez-Gonzalez, B..

4 recordsLinked to original sources

bioRxiv2025

HDAC1 has a role in double strand break repair by regulating γH2AX signalling

Genome integrity is challenged by DNA damage. DNA double-strand breaks are the most harmful DNA lesions as they block DNA replication and transcription leading to chromosome reorganisations or cell death if not properly repaired. In addition, increasing evidence points to chromatin as a relevant modulator of the efficiency of repair in eukaryotes. Here, we show that inhibition or depletion of human histone deacetylase 1 (HDAC1) regulates DSB repair by controlling the phosphorylation of H2AX, an early step of the DNA damage response. Thus, DSB repair is regulated by a crosstalk between histone acetylation and phosphorylation. Our study provides evidence that histone acetylation regulates DSB signalling supporting that histone deacetylase inhibitors could enhance genotoxic treatment of cancer.

molecular biology↗

bioRxiv2024

Dbf4-Dependent Kinase Finetunes INO80 Function at Chromosome Replication Origins

The highly conserved Dbf4-Dependent Kinase (DDK) plays a pivotal role in the nucleus during S phase, where it directly phosphorylates the replicative helicase, the minichromosome maintenance (MCM) complex. This leads to the initiation of chromosome replication. However, aside from the MCM complex, few other targets have been identified to date, leaving DDK an understudied kinase. Here, we describe a two-pronged mass spectrometry-based approach and define the nuclear DDK-dependent phosphoproteome, which consists of approximately 400 phosphorylation events. Within this network, we found that DDK directly phosphorylates the Arp8 subunit of the multi-subunit chromatin remodeler complex INO80. Arp8 phosphorylation stabilises INO80s intramolecular complex integrity, which finetunes its nucleosome spacing activity at replication origins. This adjustment of origin chromatin architecture stimulates replication and is important for the response to replication stress. Our results represent a significant advance in our understanding of the molecular mechanisms underlying the regulation of replication origins.

biochemistry↗

bioRxiv2020

A CDK-regulated chromatin segregase promoting chromosome replication

The replication of chromosomes during S phase is critical for cellular and organismal function. Replicative stress can result in genome instability, which is a major driver of cancer. Yet how chromatin is made accessible during eukaryotic DNA synthesis is poorly understood. Here, we report the identification of a novel class of chromatin remodeling enzyme, entirely distinct from classical SNF2-ATPase family remodelers. Yta7 is a AAA+-ATPase that assembles into ~ 1 MDa hexameric complexes capable of segregating histones from DNA. Yta7 chromatin segregase promotes chromosome replication both in vivo and in vitro. Biochemical reconstitution experiments using purified proteins revealed that Yta7s enzymatic activity is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK). S-CDK phosphorylation stimulates ATP hydrolysis by Yta7, promoting nucleosome disassembly and chromatin replication. Our results present a novel mechanism of how cells orchestrate chromatin dynamics in co-ordination with the cell cycle machinery to promote genome duplication during S phase.

biochemistry↗

bioRxiv2020

Harmful DNA:RNA hybrids are formed in cis and in a Rad51-independent manner

DNA:RNA hybrids constitute a well-known source of recombinogenic DNA damage. The current literature is in agreement with DNA:RNA hybrids being produced co-transcriptionally by the invasion of the nascent RNA molecule produced in cis with its DNA template. However, it has also been suggested that recombinogenic DNA:RNA hybrids could be facilitated by the invasion of RNA molecules produced in trans in a Rad51-mediated reaction. Here, we tested the possibility that such DNA:RNA hybrids produced in trans constitute a source of recombinogenic DNA damage taking advantage of Rad51-independent single-strand annealing recombination assays and new constructs designed to induce expression of mRNA transcripts in trans in the yeast Saccharomyces cerevisiae. We show that unscheduled and recombinogenic DNA:RNA hybrids are formed in cis during transcription and in a Rad51-independent manner.

molecular biology↗