Chromatin Challenges during DNA Replication and Repair

Groth, Anja; Rocha, Walter; Verreault, Alain; Almouzni, Geneviève

doi:10.1016/j.cell.2007.01.030

Cited by 674 publications

(592 citation statements)

References 116 publications

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“…DNA repair is no exception, and dynamic changes in chromatin condensation and accompanying histone marks have been recognized as inevitable DDR pathways [15,[75][76][77][78][79][80]. Here, too, the DDR relies on recruitment of existing players in the chromatin organization arena [32][33][34][75][76][77][78][79][81][82][83][84][85].…”

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

“…Information about the interface between the DDR and chromatin organization is rapidly accumulating [75,76,78,108,[118][119][120]]. An early, extremely rapid process at damage sites is the CK2-mediated phosphorylation and eviction of the heterochromatin protein 1 (HP1) [121].…”

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

“…Thus, the two histone monoubiquitylations may play opposing roles in the dynamics of chromatin organization: H2Bub in the immediate vicinity of DSBs, and H2Aub farther away from these lesions. Indeed, despite the apparent analogy between the two modifications, H2Aub, at the opposing side of the nucleosomal surface, does not lead to chromatin fiber decompaction [70].Information about the interface between the DDR and chromatin organization is rapidly accumulating [75,76,78,108,[118][119][120]]. An early, extremely rapid process at damage sites is the CK2-mediated phosphorylation and eviction of the heterochromatin protein 1 (HP1) [121].…”

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RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

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Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

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RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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“…This dynamic nature has been confirmed by more recent cell and molecular studies. First, essential processes, such as gene transcription, DNA replication and repair, all involve disruption and reassembly of chromatin structure [9,10]. Second, Fluorescence recovery after photobleaching (FRAP) studies have shown that most chromatin-bound proteins are not statically bound, but exhibit relatively high "off" and "on" rates, even in supposedly "closed" heterochromatin [11,12].…”

Section: The Dynamic and Stochastic Properties Of Chromatinmentioning

confidence: 99%

Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

140

102

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Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

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“…Another scenario could be that the hMOFdepleted cells may have a defective S phase checkpoint, therefore leading to the observed G 2 /M accumulation. We can speculate that a hMOF-dependent reduction of H4K16 acetylation, a modification that reaches its highest levels during mid-S phase (Rice et al, 2002), could affect DNA replication, as during this phase a tight co-ordination between DNA replication and preservation of epigenetic integrity must be achieved (Groth et al, 2007). An alternative explanation would be that loss of hMOF could impair the cell's ability to repair DNA, thereby activating the G 2 /M checkpoint.…”

Section: Hmof In the Dna Damage Responsementioning

confidence: 99%

Males absent on the first (MOF): from flies to humans

2007

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Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G 2 /M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed.

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Chromatin Challenges during DNA Replication and Repair

Cited by 674 publications

References 116 publications

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

Aging by epigenetics—A consequence of chromatin damage?

Males absent on the first (MOF): from flies to humans

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