Repair of exogenous DNA double-strand breaks promotes chromosome synapsis in SPO11-mutant mouse meiocytes, and is altered in the absence of HORMAD1

Carofiglio, Fabrizia; Sleddens-Linkels, Esther; Wassenaar, Evelyne; Inagaki, Akiko; Cappellen, Wiggert A. van; Grootegoed, J. Anton; Tóth, Attila; Baarends, Willy M.

doi:10.1016/j.dnarep.2018.01.007

Cited by 39 publications

(42 citation statements)

References 83 publications

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Section: Discussionmentioning

confidence: 89%

“…The new role we define for HORMAD1 in promoting DSB repair in cancer cells differs from how Hormad1 impacts repair radiation-induced DSB in mouse meiotic cells 50 . Carofiglio and colleagues examined repair kinetics of IR-induced DSB in Spo11/Hormad1 double knockout mice 50 . Those workers observed fewer DSB repair foci remaining 24 h and 48 h after irradiation in Spo11 −/− /Hormad −/− double knockout spermatocytes, when compared to Spo11 −/− spermatocytes indicating that Hormad1 inhibits repair of exogenous DSBs in meiocytes 50 .…”

Section: Discussionmentioning

confidence: 89%

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The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

Gao

Kardos

Yang

et al. 2018

Sci Rep

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The Cancer/Testes (CT) Antigen HORMAD1 is germ cell-restricted and plays developmental roles in generation and processing of meiotic DNA Double Strand Breaks (DSB). Many tumors aberrantly overexpress HORMAD1 yet the potential impact of this CT antigen on cancer biology is unclear. We tested a potential role of HORMAD1 in genome maintenance in lung adenocarcinoma cells. We show that HORMAD1 re-distributes to nuclear foci and co-localizes with the DSB marker γH2AX in response to ionizing radiation (IR) and chemotherapeutic agents. The HORMA domain and C-term disordered oligomerization motif are necessary for localization of HORMAD1 to IR-induced foci (IRIF). HORMAD1-depleted cells are sensitive to IR and camptothecin. In reporter assays, Homologous Recombination (HR)-mediated repair of targeted ISce1-induced DSBs is attenuated in HORMAD1-depleted cells. In Non-Homologous End Joining (NHEJ) reporter assays, HORMAD1-depletion does not affect repair of ISce1-induced DSB. Early DSB signaling events (including ATM phosphorylation and formation of γH2AX, 53BP1 and NBS1 foci) are intact in HORMAD1-depleted cells. However, generation of RPA-ssDNA foci and redistribution of RAD51 to DSB are compromised in HORMAD1-depleted cells, suggesting that HORMAD1 promotes DSB resection. HORMAD1-mediated HR is a neomorphic activity that is independent of its meiotic partners (including HORMAD2 and CCDC36. Bioinformatic analysis of TCGA data show that similar to known HR pathway genes HORMAD1 is overexpressed in lung adenocarcinomas. Overexpression of HR genes is associated with specific mutational profiles (including copy number variation). Taken together, we identify HORMAD1-dependent DSB repair as a new mechanism of radioresistance and a probable determinant of mutability in lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

Gao

Kardos

Yang

et al. 2018

Sci Rep

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“…In order to determine whether the abnormal ©H2AX pattern was due to an increase in the number of DSBs or delayed repair, we assayed for homologous recombination repair markers like Replication Protein A (RPA32). The localization pattern and number of RPA foci on SC axis across meiotic stages are highly regulated and are used as bona-fide markers to assess repair kinetics/efficiency [47, 48]. We observed that while the numbers of RPA foci on autosomes in the early pachytene stage were similar in Sirt1 WT and Sirt1 Δmeio cells (Figs 4A and 4B), foci counts at late pachytene were 3-fold higher in Sirt1 Δmeio cells when compared to Sirt1 WT (Figs 4C and 4D).…”

Section: Resultsmentioning

confidence: 99%

NAD⁺-dependent deacetylase SIRT1 is essential for meiotic progression and controls repair-recombination efficiency

Kaul

Deota

Fulzele

et al. 2019

Preprint

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23Meiotic components and their functions have been extensively studied. Yet, the 24 interplay between molecular factors and regulation of their functions that is brought 25 about by post-translational modifications, specifically (de)-acetylation, is not well 26 characterized. SIRT1, a NAD + -dependent deacetylase has been previously shown to 27 be necessary for spermatogenesis. However, whether it has any role to play in 28 mammalian meiosis remains to be uncovered. Our findings identify SIRT1 as a key 29 determinant of meiotic progression. Knocking out SIRT1 specifically in meiocytes 30 (SIRT1 meio ) led to a delay in progression through pachytene and repair of double 31 strand breaks. Interestingly, despite these deficits, meiotic loss of SIRT1 did not 32 affect synapsis nor did it lead to pachytene arrest or apoptosis. Moreover, our results 33 demonstrate that SIRT1 is required for regulating crossover frequency and its 34 absence results in higher crossover events. Therefore, our study brings to the fore a 35 novel regulatory factor/mechanism that is necessary for coupling of synapsis and 36 recombination. This is noteworthy since mutations in core meiotic components result 37 in gross defects in synapsis, repair and recombination, and very few studies have 38 reported the differential regulation of these processes. Further, exposing SIRT1 meio 39 to low/moderate doses of -irradiation indicated that SIRT1 might be involved in 40 eliciting recombination checkpoint arrest and in its absence pachytene cells progress 41 to diplotene stage, unlike in the SIRT1 WT mice. Importantly, exogenous damage 42 resulted in enhanced retention of H2AX in SIRT1 meio diplotene cells, reiterating the 43 critical role that SIRT1 plays in regulating repair efficiency/kinetics. Molecularly, we 44 find that SIRT1 interacts with MRN complex and lack of SIRT1 causes 45 hyperacetylation of several non-histone proteins including the MRN components. 46Given that SIRT1 meio mice mimic MRN hypomorphs, we propose that SIRT1-3 47 dependent deacetylation of these proteins is crucial for normal meiotic progression. 48Taken together, our study uncovers a previously unappreciated role of SIRT1 in 49 meiotic progression. 51 Author Summary 52Meiosis is a key process in germ cell development that is essential for generating 53 genetic diversity via recombination. It involves precise spatio-temporal orchestration 54 of various molecular events such as chromosomal synapsis, repair and 55 recombination. Whereas the core meiotic components are well known, upstream 56 factors that might be important for regulating their functions and also couple the 57 downstream processes are less explored. In this paper, we report that SIRT1, a 58 NAD + -dependent deacetylase, is necessary for meiotic progression by identifying its 59 role in coupling of synapsis and recombination. By generating a meiosis specific 60 knockout of SIRT1, we show that its absence in spermatocytes leads to 61 inefficient/delayed repair and progression through pachytene. We have a...

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“…In mice, NCOs are the prevalent outcome of the repair of programmed meiotic DSBs with the NCOs/COs overall ratio 9:1, based on cytological data and sperm typing 7,49,50 . Despite their prevalence and assumed functional significance for meiotic synapsis of homologous chromosomes 10,11,50 little is known about their genome-wide distribution and properties. In this study, we used whole-genome sequencing to detect and characterize a unique dataset of 95 NCO events in 10 mouse chromosomes using the B6.PWD-Chr # panel of mouse consomic strans.…”

Section: Discussionmentioning

confidence: 99%

Chromosome-wide distribution and characterization of intersubspecific meiotic noncrossovers in mice

Gergelits

Parvanov

Šimeček

et al. 2019

Preprint

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11During meiosis, the recombination-initiating DNA double-strand breaks (DSBs) are repaired 12 by crossovers or noncrossovers (gene conversions). While crossovers are easily detectable, 13 the noncrossover identification is hampered by the small size of their converted tracts and 14 the necessity of sequence polymorphism to detect them. We report identification and 15 characterization of a mouse chromosome-wide set of noncrossovers by NGS sequencing of 16 10 mouse chromosome substitution strains. Based on 94 identified noncrossovers we 17 determined the mean length of a conversion tract to be 32 basepairs. The spatial 18 chromosome-wide distribution of noncrossovers and crossovers significantly differed, 19 though both sets overlapped the known hotspots of PRDM9-directed histone methylation 20 and DNA DSBs, thus proving their origin in the standard DSB repair pathway. A significant 21 deficit of noncrossovers descending from asymmetric DSBs pointed to sister chromatids as 22 an alternative template for their repair. The finding has implications for the molecular 23 mechanism of hybrid sterility in mice. 24

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Repair of exogenous DNA double-strand breaks promotes chromosome synapsis in SPO11-mutant mouse meiocytes, and is altered in the absence of HORMAD1

Cited by 39 publications

References 83 publications

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

NAD⁺-dependent deacetylase SIRT1 is essential for meiotic progression and controls repair-recombination efficiency

Chromosome-wide distribution and characterization of intersubspecific meiotic noncrossovers in mice

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Repair of exogenous DNA double-strand breaks promotes chromosome synapsis in SPO11-mutant mouse meiocytes, and is altered in the absence of HORMAD1

Cited by 39 publications

References 83 publications

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

NAD+-dependent deacetylase SIRT1 is essential for meiotic progression and controls repair-recombination efficiency

Chromosome-wide distribution and characterization of intersubspecific meiotic noncrossovers in mice

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NAD⁺-dependent deacetylase SIRT1 is essential for meiotic progression and controls repair-recombination efficiency