LINC complexes promote homologous recombination in part through inhibition of nonhomologous end joining

Lawrence, Katherine S.; Tapley, Erin C.; Cruz, Victor E.; Li, Qianyan; Aung, Kayla; Hart, Kevin C.; Schwartz, Thomas; Starr, Daniel A.; Engebrecht, JoAnne

doi:10.1083/jcb.201604112

Cited by 46 publications

(61 citation statements)

References 102 publications

(189 reference statements)

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“…Intriguingly, although CHD4 knockdown significantly impairs HR (Pan et al, 2012), other forms of repair appear to remain intact, as NHEJ can effectively repair DSBs in CHD4 depleted cells (Qi et al, 2016 (Lemmens et al, 2013). However, there are several reports of spurious NHEJ activation in scenarios wherein HR is compromised due to defects in either SC assembly or RAD-51 processing (Lawrence et al, 2016;Martin et al, 2005;Smolikov et al, 2007;Yin and Smolikove, 2013).…”

Section: Mi2 Deficient Worms With Regard To Dsb Repair (Figures 4-5)mentioning

confidence: 99%

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

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Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination. We discovered that loss of either CHD-3 or LET-418 results in elevated p53-dependent germline apoptosis, which relies on the activation of the conserved checkpoint kinase CHK-1. Consistent with these findings, chd-3 and let-418 mutants produce a reduced number of offspring, indicating a role for Mi2 in forming viable gametes. When Mi2 function is compromised, persisting recombination intermediates are detected in late pachytene nuclei, indicating a failure in the timely repair of DSBs. Intriguingly, our data indicate that in Mi2 mutant germ lines, a subset of DSBs are repaired by non-homologous end joining, which manifests as chromosomal fusions.We find that meiotic defects are exacerbated in Mi2 mutants lacking CKU-80, as evidenced by increased recombination intermediates, corpses, and defects in chromosomal integrity. Taken together, our findings support a model wherein the C. elegans Mi2 complex maintains genomic integrity through reinforcement of a chromatin landscape suitable for homology-driven repair mechanisms.4

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Section: Mi2 Deficient Worms With Regard To Dsb Repair (Figures 4-5)mentioning

confidence: 99%

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

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“…Knowledge is lacking with respect to the contributions of different pathways to repair of DSBs not destined to form crossovers and whether their use differs in the sexes. During C. elegans and Drosophila oogenesis, the nonhomologous end joining (NHEJ) pathway for DSB repair is actively inhibited early in meiosis (JOYCE et al 2012;LEMMENS et al 2013;YIN AND SMOLIKOVE 2013;LAWRENCE et al 2016;GIRARD et al 2018) but NHEJ and other pathways, including theta-mediated end joining and single strand annealing, serve as backups to ensure that all DSBs are repaired in late pachytene before the meiotic divisions (SMOLIKOV et al 2007;MACAISNE et al 2018). A recent study examining the repair of DNA breaks induced by radiation suggests that mouse spermatocytes switch to a somatic-like repair mode at pachytene, temporarily engaging NHEJ and then HR to repair the damage (ENGUITA-MARRUEDO et al 2019).…”

Section: Introductionmentioning

confidence: 99%

C. elegans BRC-1-BRD-1 functions at an early step of DSB processing and inhibits supernumerary crossovers during male meiosis

Engebrecht

Li²,

Hariri³

2020

Preprint

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Meiosis is regulated in a sex-specific manner to produce two distinct gametes, sperm and oocytes, for sexual reproduction. To determine how meiotic recombination is regulated in spermatogenesis, we analyzed the meiotic phenotypes of mutants in the tumor suppressor E3 ubiquitin ligase BRC-1-BRD-1 complex in Caenorhabditis elegans male meiosis. Unlike in mammals, this complex is not required for meiotic sex chromosome inactivation, the process whereby hemizygous sex chromosomes are transcriptionally silenced. Interestingly, brc-1 and brd-1 mutants showed meiotic recombination phenotypes that are largely opposing to those previously reported for female meiosis.Fewer meiotic recombination foci marked by the recombinase RAD-51 were observed in brc-1 and brd-1 mutants, and the reduction in RAD-51 foci can be suppressed by mutation of nonhomologous end joining proteins. We show that concentration of BRC-1-BRD-1 to sites of meiotic recombination is dependent on DNA end resection, suggesting that BRC-1-BRD-1 regulates the processing of meiotic double strand breaks to promote repair by homologous recombination, similar to a role for the complex in somatic cells. We also show that BRC-1-BRD-1 is important to promote progeny viability when male meiosis is perturbed by mutations that block the pairing and synapsis of different chromosome pairs, although the complex is not required to stabilize the RAD-51 filament as in female meiosis under the same conditions. Analyses of crossover designation and formation reveal that BRC-1-BRD-1 inhibits supernumerary crossovers when meiosis is perturbed. Together, our findings suggest that BRC-1-BRD-1 regulates different aspects of meiotic recombination in male and female meiosis.

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“…The LINC complex performs diverse functions, including nuclear shaping and positioning [29], maintenance of the centrosome–nucleus connection [30], DNA repair [31,32], nuclear membrane spacing [11], cell migration [28,29,33,34,35], and moving chromosomes within the nucleus during meiosis [36]. In addition, lamins play various roles such as maintenance of nuclear integrity, cell cycle regulation, mechanotransduction, cellular signalling, and DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Implications for Diverse Functions of the LINC Complexes Based on the Structure

Hieda

2017

Cells

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The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the outer and inner nuclear membrane protein families Klarsicht, Anc-1, and Syne homology (KASH), and Sad1 and UNC-84 (SUN) homology domain proteins. Increasing evidence has pointed to diverse functions of the LINC complex, such as in nuclear migration, nuclear integrity, chromosome movement and pairing during meiosis, and mechanotransduction to the genome. In metazoan cells, the nuclear envelope possesses the nuclear lamina, which is a thin meshwork of intermediate filaments known as A-type and B-type lamins and lamin binding proteins. Both of lamins physically interact with the inner nuclear membrane spanning SUN proteins. The nuclear lamina has also been implicated in various functions, including maintenance of nuclear integrity, mechanotransduction, cellular signalling, and heterochromatin dynamics. Thus, it is clear that the LINC complex and nuclear lamins perform diverse but related functions. However, it is unknown whether the LINC complex–lamins interactions are involved in these diverse functions, and their regulation mechanism has thus far been elusive. Recent structural analysis suggested a dynamic nature of the LINC complex component, thus providing an explanation for LINC complex organization. This review, elaborating on the integration of crystallographic and biochemical data, helps to integrate this research to gain a better understanding of the diverse functions of the LINC complex.

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LINC complexes promote homologous recombination in part through inhibition of nonhomologous end joining

Abstract: DNA repair is critical for genome integrity. Lawrence et al. reveal a role for a novel complex that links the nucleus to microtubules to promote accurate repair through both inhibition of error-prone nonhomologous end joining and promotion of homologous recombination.

Cited by 46 publications

References 102 publications

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

C. elegans BRC-1-BRD-1 functions at an early step of DSB processing and inhibits supernumerary crossovers during male meiosis

Implications for Diverse Functions of the LINC Complexes Based on the Structure

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