Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Abstract

SummaryComponents of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

“…Furthermore, SETD1A has been shown to promote cell cycle progression by activating the expression of micro RNAs that suppress the antiproliferative gene BTG2, which plays a role in the transition between the G1 and S phase of the cell cycle 11 . Finally, H3K4 methylation by SETD1A is crucial in maintaining genome stability, especially during DNA replication, by protecting newly-replicated DNA from degradation 12 .…”

Control of Hematopoietic Stem and Progenitor Cell Function Through Epigenetic Regulation of Energy Metabolism and Genome Integrity

“…As DPY30-associated H3K4 methylation is functionally important for chromatin accessibility (Yang et al, 2018), it may regulate the efficiency of DNA repair by promoting the accessibility of DNA repair proteins. In addition to facilitating DNA repair, H3K4 methylation may also protect nascent DNA from degradation in replication stress (Higgs et al, 2018), thereby contributing to the maintenance of genome stability. Our results also suggest that it is the response to DNA damage, rather than the damage itself, that results in the inactivity of HSPCs.…”

“…As DDR occurs in the context of chromatin, it is thus governed by epigenetic mechanisms regulating chromatin structure and accessibility (Lukas et al, 2011). In addition to the well-established association with active gene expression, a role of H3K4 methylation in regulating genome stability is also gradually emerging (Burman et al, 2015;Faucher and Wellinger, 2010;Herbette et al, 2017;Higgs et al, 2018).…”

Knockdown of KDM1A suppresses tumour migration and invasion by epigenetically regulating the TIMP1/MMP9 pathway in papillary thyroid cancer

“…Histone methylation mainly acts on lysine residues and regulates either the repression or activation of gene expression. Histone lysine methylation is reversibly modulated by specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) and is involved in various biological processes and diseases in humans . As the first demethylase discovered, KDM1A is the best characterized KDM.…”