scholarly journals Sumo-mediated recruitment allows timely function of the Yen1 nuclease in mitotic cells

2021 ◽  
Author(s):  
Hugo Dorison ◽  
Ibtissam Talhaoui ◽  
Gerard Mazón
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Genome Instability ◽  
Covalent Binding ◽  
Critical Role ◽  
Strand Break ◽  
Damage Response ◽  
Covalently Linked ◽  
Break Formation

The modification of DNA damage response proteins with Sumo is an important mechanism to orchestrate a timely and orderly recruitment of repair factors to damaged sites. After replication stress and double-strand break formation a number of repair factors are Sumoylated and interact with other Sumoylated factors, including the nuclease Yen1. Yen1 plays a critical role to ensure genome stability and unperturbed chromosome segregation by removing covalently linked DNA intermediates that are formed by homologous recombination. Here we show how this important role of Yen1 is dependent on interactions mediated by non-covalent binding to Sumoylated partners. Mutations in the motifs that allow Sumo-mediated recruitment of Yen1 impair its ability to resolve DNA intermediates and result in increased genome instability and chromosome missegregation.

scholarly journals SIRT7: a sentinel of genome stability

Open Biology ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 210047
Author(s):  
Ming Tang ◽  
Huangqi Tang ◽  
Bo Tu ◽  
Wei-Guo Zhu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Biological Function ◽  
Critical Role ◽  
Class Iii ◽  
Cellular Processes ◽  
The Past ◽  
Damage Response ◽  
Normal Gene

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

scholarly journals Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Dorota Rousova ◽  
Vaishnavi Nivsarkar ◽  
Veronika Altmannova ◽  
Vivek B Raina ◽  
Saskia K Funk ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Protein Complexes ◽  
Strand Break ◽  
Yeast Genetics ◽  
Biochemical Basis ◽  
Dna Double Strand Break ◽  
Break Formation ◽  
Insight Into

In meiosis, DNA double strand break (DSB) formation by Spo11 initiates recombination and enables chromosome segregation. Numerous factors are required for Spo11 activity, and couple the DSB machinery to the development of a meiosis-specific “axis-tethered loop” chromosome organization. Through in vitro reconstitution and budding yeast genetics we here provide architectural insight into the DSB machinery by focussing on a foundational DSB factor, Mer2. We characterise the interaction of Mer2 with the histone reader Spp1, and show that Mer2 directly associates to nucleosomes, likely highlighting a contribution of Mer2 to tethering DSB factors to chromatin. We reveal the biochemical basis of Mer2 association with Hop1, a HORMA domain-containing chromosomal axis factor. Finally, we identify a conserved region within Mer2 crucial for DSB activity, and show that this region of Mer2 interacts with the DSB factor Mre11. In combination with previous work, we establish Mer2 as a keystone of the DSB machinery by bridging key protein complexes involved in the initiation of meiotic recombination.

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

2021 ◽  
Author(s):  
Bing Sun ◽  
McLean Sherrin ◽  
Richard Roy
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Germ Line ◽  
Critical Role ◽  
Significant Proportion ◽  
Loop Formation ◽  
C Elegans ◽  
Chromatin Activation ◽  
Acute Starvation

Abstract During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

scholarly journals Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

2018 ◽  
Vol 19 (8) ◽  
pp. 2389 ◽  
Author(s):  
Md. Hossain ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Strand Break ◽  
Single Strand ◽  
Genome Integrity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response ◽  
End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

scholarly journals cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence

2021 ◽  
Author(s):  
Xiaocui Li ◽  
Xiaojuan Li ◽  
Chen Xie ◽  
Sihui Cai ◽  
Mengqiu Li ◽  
...  
Keyword(s):  
Genome Stability ◽  
Mitotic Chromosome ◽  
Replicative Senescence ◽  
Genome Instability ◽  
Strand Break ◽  
End Joining ◽  
Dsb Repair ◽  
End To End ◽  
Non Homologous End Joining ◽  
Sting Pathway

AbstractAs a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

scholarly journals The balancing act of R-loop biology: The good, the bad, and the ugly

2019 ◽  
Vol 295 (4) ◽  
pp. 905-913 ◽  
Author(s):  
Youssef A. Hegazy ◽  
Chrishan M. Fernando ◽  
Elizabeth J. Tran
Keyword(s):  
Genome Instability ◽  
Strand Break ◽  
Biological Processes ◽  
Physiological Importance ◽  
Future Goals ◽  
Dna Double Strand Break ◽  
Positive Functions ◽  
Acid Structure

An R-loop is a three-stranded nucleic acid structure that consists of a DNA:RNA hybrid and a displaced strand of DNA. R-loops occur frequently in genomes and have significant physiological importance. They play vital roles in regulating gene expression, DNA replication, and DNA and histone modifications. Several studies have uncovered that R-loops contribute to fundamental biological processes in various organisms. Paradoxically, although they do play essential positive functions required for important biological processes, they can also contribute to DNA damage and genome instability. Recent evidence suggests that R-loops are involved in a number of human diseases, including neurological disorders, cancer, and autoimmune diseases. This review focuses on the molecular basis for R-loop–mediated gene regulation and genomic instability and briefly discusses methods for identifying R-loops in vivo. It also highlights recent studies indicating the role of R-loops in DNA double-strand break repair with an updated view of much-needed future goals in R-loop biology.

scholarly journals Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation

2010 ◽  
Vol 30 (19) ◽  
pp. 4722-4731 ◽  
Author(s):  
Steven L. Sanders ◽  
Ahmad R. Arida ◽  
Funita P. Phan
Keyword(s):  
Dna Damage ◽  
Histone Modification ◽  
Genome Stability ◽  
Strand Break ◽  
Binding Activity ◽  
Critical Element ◽  
Checkpoint Control ◽  
Ionizing Irradiation ◽  
Checkpoint Activation ◽  
Damage Response

ABSTRACT Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability.

The complex matter of DNA double-strand break detection

2003 ◽  
Vol 31 (1) ◽  
pp. 40-44 ◽  
Author(s):  
J.M. Bradbury ◽  
S.P. Jackson
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Strand Break ◽  
Damage Sensing ◽  
Dna Double Strand Break ◽  
Mre11 Complex ◽  
Damage Response ◽  
Radiation Induced ◽  
Dna Damage Signalling ◽  
Complex Matter

To maintain genomic stability, despite constant exposure to agents that damage DNA, eukaryotic cells have developed elaborate and highly conserved pathways of DNA damage sensing, signalling and repair. In this review, we concentrate mainly on what we know about DNA damage sensing with particular reference to Lcd1p, a yeast protein that functions early in DNA damage signalling, and MDC1 (mediator of DNA damage checkpoint 1), a recently identified human protein that may be involved in recruiting the MRE11 complex to radiation-induced nuclear foci. We describe a model for the DNA damage response in which factors are recruited sequentially to sites of DNA damage to form complexes that can amplify the original signal and propagate it to the multitude of response pathways necessary for genome stability.

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