Histone acetyltransferase 1 is required for DNA replication fork function and stability

Garcia, Paula A. Agudelo; Lovejoy, Callie M.; Nagarajan, Prabakaran; Park, Dongju; Popova, Liudmila V.; Freitas, Michael A.; Parthun, Mark R.

doi:10.1074/jbc.ra120.013496

Cited by 26 publications

(20 citation statements)

References 80 publications

(80 reference statements)

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“…The transient physical association of HAT1 with newly replicated DNA opens up the possibility that HAT1 is directly involved in the regulation of H3 K9me2/3 dynamics on nascent chromatin (Figure 7A ) ( 38 , 69 , 92 ). The presence of HAT1 on nascent chromatin may sterically block the activity of KMTs, as the RBBP7/HAT2 subunit of the HAT1 complex also binds the NH 2 -terminal tail of histone H3 ( 93 ).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones

Popova

Nagarajan

Lovejoy

et al. 2021

Nucleic Acids Research

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A central component of the epigenome is the pattern of histone post-translational modifications that play a critical role in the formation of specific chromatin states. Following DNA replication, nascent chromatin is a 1:1 mixture of parental and newly synthesized histones and the transfer of modification patterns from parental histones to new histones is a fundamental step in epigenetic inheritance. Here we report that loss of HAT1, which acetylates lysines 5 and 12 of newly synthesized histone H4 during replication-coupled chromatin assembly, results in the loss of accessibility of large domains of heterochromatin, termed HAT1-dependent Accessibility Domains (HADs). HADs are mega base-scale domains that comprise ∼10% of the mouse genome. HAT1 globally represses H3 K9 me3 levels and HADs correspond to the regions of the genome that display HAT1-dependent increases in H3 K9me3 peak density. HADs display a high degree of overlap with a subset of Lamin-Associated Domains (LADs). HAT1 is required to maintain nuclear structure and integrity. These results indicate that HAT1 and the acetylation of newly synthesized histones may be critical regulators of the epigenetic inheritance of heterochromatin and suggest a new mechanism for the epigenetic regulation of nuclear lamina-heterochromatin interactions.

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Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones

Popova

Nagarajan

Lovejoy

et al. 2021

Nucleic Acids Research

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“…Conversely, depletion of CHD4 was shown to restore fork protection in BRCA2-deficient cells by suppressing the recruitment of MRE11 at HU-stalled forks (Figure 2B ) ( 37 ). Similarly, the loss of the histone acetyl transferase HAT1, primarily associated with increased chromatin accessibility, also renders stalled forks susceptible to degradation (Figure 2A ) ( 74 ). Another fork protection factor putatively dependent on chromatin accessibility is FANCJ.…”

Section: Emerging Determinants Of Fork Protectionmentioning

confidence: 99%

The emerging determinants of replication fork stability

Thakar

Moldovan

2021

Nucleic Acids Research

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A universal response to replication stress is replication fork reversal, where the nascent complementary DNA strands are annealed to form a protective four-way junction allowing forks to avert DNA damage while replication stress is resolved. However, reversed forks are in turn susceptible to nucleolytic digestion of the regressed nascent DNA arms and rely on dedicated mechanisms to protect their integrity. The most well studied fork protection mechanism involves the BRCA pathway and its ability to catalyze RAD51 nucleofilament formation on the reversed arms of stalled replication forks. Importantly, the inability to prevent the degradation of reversed forks has emerged as a hallmark of BRCA deficiency and underlies genome instability and chemosensitivity in BRCA-deficient cells. In the past decade, multiple factors underlying fork stability have been discovered. These factors either cooperate with the BRCA pathway, operate independently from it to augment fork stability in its absence, or act as enablers of fork degradation. In this review, we examine these novel determinants of fork stability, explore the emergent conceptual underpinnings underlying fork protection, as well as the impact of fork protection on cellular viability and cancer therapy.

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“…Histone acetyltransferase 1 (HAT1) catalyses the acetylation of histone H4 at lysine 5 and lysine 12 and this activity is important in the processing of newly deposited histones during replication ( Nagarajan et al, 2013 ). Depletion of HAT1 results in replication stalling and sensitivity of cells to replication stress induced by HU ( Nagarajan et al, 2013 ; Agudelo Garcia et al, 2020 ). The importance of HAT1 in maintaining genome stability during replication stress is due to its roles in protecting stalled forks from degradation by MRE11 ( Agudelo Garcia et al, 2020 ).…”

Section: Role Of the Local Chromatin Environment During Replication Stressmentioning

confidence: 99%

Chromatin and Nuclear Dynamics in the Maintenance of Replication Fork Integrity

Wootton

Soutoglou

2021

Front. Genet.

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Replication of the eukaryotic genome is a highly regulated process and stringent control is required to maintain genome integrity. In this review, we will discuss the many aspects of the chromatin and nuclear environment that play key roles in the regulation of both unperturbed and stressed replication. Firstly, the higher order organisation of the genome into A and B compartments, topologically associated domains (TADs) and sub-nuclear compartments has major implications in the control of replication timing. In addition, the local chromatin environment defined by non-canonical histone variants, histone post-translational modifications (PTMs) and enrichment of factors such as heterochromatin protein 1 (HP1) plays multiple roles in normal S phase progression and during the repair of replicative damage. Lastly, we will cover how the spatial organisation of stalled replication forks facilitates the resolution of replication stress.

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Histone acetyltransferase 1 is required for DNA replication fork function and stability

Cited by 26 publications

References 80 publications

Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones

Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones

The emerging determinants of replication fork stability

Chromatin and Nuclear Dynamics in the Maintenance of Replication Fork Integrity

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