Histone H2A variants: Diversifying chromatin to ensure genome integrity

Oberdoerffer, Philipp; Miller, Kyle M.

doi:10.1016/j.semcdb.2022.03.011

Cited by 32 publications

(22 citation statements)

References 182 publications

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“…Given that PAR chain length and PARP activation regulate the association of KDM5A with DSBs, it is worth testing how loss of macroH2A1.1 specifically may alter KDM5A-dependent functions. Given that macroH2A1.1 cells display limited defects in HR, unlike KDM5A-and macroH2A1.2-deficient cells, we favor the idea that macroH2A1.2 specifically functions along KDM5A in the DDR while macroH2A1.1 is involved in other DDR pathways, including those involving Alt-NHEJ, single strand break (SSB) repair, and NHEJ (reviewed in [83] ).…”

Section: Kdm5a As a Par Effectormentioning

confidence: 89%

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

2022

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The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNA repair. Indeed, KDM5A engages poly(ADP-ribose) (PAR) chains at damage sites through a previously uncharacterized coiled-coil domain, a novel binding mode for PAR interactions. While KDM5A is a well-known transcriptional regulator, its function in DNA repair is only now emerging.Here we review the molecular mechanisms that regulate this PARP1-macroH2A1.2-KDM5A axis in DNA damage and consider the potential involvement of this pathway in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA-based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies.

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Section: Kdm5a As a Par Effectormentioning

confidence: 89%

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

2022

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“…81 For a discussion of the roles of H2A variants in DNA repair, we refer readers to a recent review by Oberdoerffer and Miller. 82 H2A.X guards genome integrity in lymphocytes H2A.X can be regarded as an intermediate between a replication-coupled histone and a histone variant. 80 It can be incorporated into chromatin in a replication-coupled manner, which explains its broad genome-wide distribution.…”

Section: Histone Variantsmentioning

confidence: 99%

Histone Variants and Their Chaperones in Hematological Malignancies

et al. 2023

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Epigenetic regulation occurs on the level of compacting DNA into chromatin. The functional unit of chromatin is the nucleosome, which consists of DNA wrapped around a core of histone proteins. While canonical histone proteins are incorporated into chromatin through a replication-coupled process, structural variants of histones, commonly named histone variants, are deposited into chromatin in a replication-independent manner. Specific chaperones and chromatin remodelers mediate the locus-specific deposition of histone variants. Although histone variants comprise one of the least understood layers of epigenetic regulation, it has been proposed that they play an essential role in directly regulating gene expression in health and disease. Here, we review the emerging evidence suggesting that histone variants have a role at different stages of hematopoiesis, with a particular focus on the histone variants H2A, H3, and H1. Moreover, we discuss the current knowledge on how the dysregulation of histone variants can contribute to hematopoietic malignancies.

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“…The H2A variants H2AX, H2AZ, and macroH2A, along with H3 variant H3.3 promote genome stability by participating in DDR pathways, as recently reviewed in ref. 130 . Defects in H2A variant function in humans have been shown to lead to diseases including cancer as well as aging.…”

Section: Histone Posttranslational Modificationsmentioning

confidence: 99%

Epigenetics, DNA damage, and aging

Soto-Palma¹,

Niedernhofer²,

Faulk³

et al. 2022

Journal of Clinical Investigation

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Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance of several types of chromatin changes. The abundance of DNA lesions (chemical perturbations to nucleotides) increases with age, as does the number of genomic mutations and transcriptional disruptions caused by replication or transcription of those lesions, respectively. At the epigenetic level, precise DNA methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, the tight regulation of histone modifications begins to unravel. The genomic instability caused by these mechanisms allows transposon element reactivation and remobilization, further mutations, gene dysregulation, and cytoplasmic chromatin fragments. This cumulative genomic instability promotes cell signaling events that drive cell fate decisions and extracellular communications known to disrupt tissue homeostasis and regeneration. In this Review, we focus on age-related epigenetic changes and their interactions with age-related genomic changes that instigate these events.

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Histone H2A variants: Diversifying chromatin to ensure genome integrity

Cited by 32 publications

References 182 publications

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

Histone Variants and Their Chaperones in Hematological Malignancies

Epigenetics, DNA damage, and aging

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