ATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis

Paiano, Jacob; Wu, Wei; Yamada, Shintaro; Sciascia, Nicholas; Callén, Elsa; Cotrim, Ana P.; Deshpande, Rajashree A.; Maman, Yaakov; Day, Amanda; Paull, Tanya T.; Nussenzweig, André

doi:10.1038/s41467-020-14654-w

Cited by 86 publications

(61 citation statements)

References 61 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Noticeably, several meiosis-associated genes, such as SPO11 , PRDM9 , DMC1 , and INCA1 , exhibited peak expression in C8 and C9. Recent studies have shown that PRDM9-mediated H3K4me3 could guide SPO11 targeting to induce DSBs 32 . Moreover, earlier formed DSBs occupy more open chromatin and are much more competent to proceed to a crossover fate, whereas later formed DSBs are likely to proceed to a non-crossover fate 21 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Zhao

Meng

et al. 2020

Cell Discov

View full text Add to dashboard Cite

Germ cells are vital for reproduction and heredity. However, the mechanisms underlying female germ cell development in primates, especially in late embryonic stages, remain elusive. Here, we performed single-cell RNA sequencing of 12,471 cells from whole fetal ovaries, and explored the communications between germ cells and niche cells. We depicted the two waves of oogenesis at single-cell resolution and demonstrated that progenitor theca cells exhibit similar characteristics to Leydig cells in fetal monkey ovaries. Notably, we found that ZGLP1 displays differentially expressed patterns between mouse and monkey, which is not overlapped with NANOG in monkey germ cells, suggesting its role in meiosis entry but not in activating oogenic program in primates. Furthermore, the majority of germ cell clusters that sharply express PRDM9 and SPO11 might undergo apoptosis after cyst breakdown, leading to germ cell attrition. Overall, our work provides new insights into the molecular and cellular basis of primate fetal ovary development at single-cell resolution.

show abstract

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Zhao

Meng

et al. 2020

Cell Discov

View full text Add to dashboard Cite

show abstract

“…This may disfavor canonical nonhomologous end-joining and promote alternative pathways that utilize microhomology 43 . However, as some DSBs remain unresected in the absence of ATM/Tel1 30-34 , deletions may also arise from joining at or very close to SPO11 cleavage positions, which would involve alternative SPO11 removal mechanisms, such as TDP2 30,44,45 . Our findings are thus consistent with multiple end-joining mechanisms being employed to repair adjacent DSBs in the absence of ATM.…”

Section: Resultsmentioning

confidence: 99%

“…The unprocessed end of the now inverted fragment joins to the third DSB at the other hotspot. This is an attractive model because it incorporates defects seen in Atm −/− mice, i.e., impaired DSB processing 30,31 , as well as invoking closely spaced DSBs. In the second model, a DSB occurs next to just one of the inverted microhomologies and resection exposes the second microhomology.…”

Section: Resultsmentioning

confidence: 99%

“…However, NHEJ can occur in mouse spermatocytes when DSBs are induced by irradiation 22-24 , and it is known to operate in C. elegans in meiotic mutants in which DSB processing 25-27 or recombination 28,29 is compromised. In principle, because ATM/Tel1 regulates meiotic DSB resection 30-34 , resection defects could favor the use of NHEJ. Moreover, the loss of ATM may cause DSBs to form at similar locations on multiple chromatids – due to the increase in DSB numbers and/or the loss of spatial control – and thus promote NHEJ by damaging repair templates.…”

mentioning

confidence: 99%

See 1 more Smart Citation

De novo deletions and duplications at recombination hotspots in mouse germlines

Lukaszewicz

Lange

Keeney

et al. 2020

Preprint

View full text Add to dashboard Cite

21Numerous DNA double-strand breaks (DSBs) arise genome-wide during meiosis to ensure 22 recombination between homologous chromosomes, which is required for gamete formation 1,2 . The 23 ATM kinase plays a central role in controlling both the number and position of DSBs 3-5 , but the 24 consequences of deregulated DSB formation have not been explored. Here we discovered that an 25 unanticipated type of DNA deletion arises at meiotic recombination hotspots in the absence of ATM. 26 Deletions form via joining of ends from two closely-spaced DSBs at adjacent hotspots or within a 27 single hotspot. Deletions are also detected in normal cells, albeit at much lower frequency, revealing 28 that the meiotic genome has a hidden potential for deletion events. Remarkably, a subset of deletions 29 contain insertions that likely originated from DNA fragments released from hotspots on other 30 chromosomes. Moreover, although deletions form primarily within one chromosome, joining between 31 homologous chromosomes is also observed. This predicts in turn gross chromosome rearrangements, 32 with evidence of damage to multiple chromatids and aborted gap repair. Thus, multiple nearby meiotic 33 DSBs are normally suppressed by ATM to protect genomic integrity. We expect the de novo germline 34 mutations we observe to affect human health and genome evolution. 35 36 37 38 39 40 41 42 43 44 45 48 hotspots 7,8 , usage of which is tightly regulated. Of all DSB hotspots (~15,000 defined in mouse), only a 49 tiny fraction (~250) experiences a DSB in any single meiosis 9-11 . DSBs are also nonrandomly dispersed 50 along chromosomes to ensure homolog pairing and recombination 3 . This quantitative and spatial 51 regulation of hotspot usage involves hierarchical and combinatorial levels of control 9,12,13 , with the 52 ATM kinase playing a central role 5,14 .53 ATM, known for its role in the DNA damage response in mitotic cells 15 , is activated by meiotic 54 DSBs to limit DSB numbers and to control hotspot usage genome-wide 4,9 . Control of DSB numbers by 55 ATM and its orthologs is conserved among organisms, although ATM-deficient mice have the largest 56 increase in DSB levels (e.g., ~10 fold compared with ~2 fold in budding yeast deficient for the ATM 57 ortholog Tel1) 5,16,17 . Control of genome-wide DSB distributions is also conserved 18 . In yeast, Tel1 58 controls DSB formation locally by suppressing double cutting, that is, simultaneous DSB formation at 59 adjacent hotspots 14,19 . This suppression is strongest at closely-spaced hotspots (<10 kb), such that in 60 the absence of Tel1, double cutting at hotspots separated by ~2 kb is more frequent than expected by 61 chance and ~10-fold higher than in wild type. The loss of this Tel1-mediated DSB suppression is 62 thought to contribute to the global increase in DSBs 18,19 . In mouse, double cutting at adjacent hotspots 63 has not been demonstrated, but potentially may be even more likely in the absence of ATM, 64 considering the extremely elevated DSB numbers. Accordingly, w...

show abstract

“…In fact, a recent study demonstrates that the MRN complex, or more specifically, NBS1, is crucial for the repair of SPO11-dependant DSBs [25]. This phenomenon is also ATM-dependent [26]. Another role discovered for SPO11 in this context is homologous chromosome pairing, i.e., facilitating the search and coupling of the correct homologous chromosomes during preleptotene, the earliest stage of meiosis [27].…”

Section: Meiosismentioning

confidence: 99%

Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States

Oster

Aqeilan

2020

Cells

View full text Add to dashboard Cite

DNA double strand breaks (DSBs) are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA. However, growing evidence continuously sheds light on the regulatory roles of programmed DSBs. Emerging studies demonstrate the roles of DSBs in processes such as T and B cell development, meiosis, transcription and replication. A significant recent progress in the last few years has contributed to our advanced knowledge regarding the functions of DSBs is the development of many next generation sequencing (NGS) methods, which have considerably advanced our capabilities. Other studies have focused on the implications of programmed DSBs on chromosomal aberrations and tumorigenesis. This review aims to summarize what is known about DNA damage in its physiological context. In addition, we will examine the advancements of the past several years, which have made an impact on the study of genome landscape and its organization.

show abstract

ATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis

Cited by 86 publications

References 61 publications

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

De novo deletions and duplications at recombination hotspots in mouse germlines

Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States

Contact Info

Product

Resources

About