DNA double-strand break repair in male germ cells during spermatogenesis and its association with male infertility development

Talibova, Günel; Bilmez, Yesim; Öztürk, Saffet

doi:10.1016/j.dnarep.2022.103386

Cited by 19 publications

(4 citation statements)

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“…The effect is small in magnitude but statistically and supposed to be biologically significant. At present, male cancer patients subjected to chemo- or radiotherapy are associated with a high risk of sub-/infertility that can be induced by spermatogonial DNA damage and apoptosis [47–49]. In this sense, our finding not only adds to the increasing knowledge about epigenetic regulation (RNA and histone methylation here) in spermatogonial genome integrity maintenance, but also lays the groundwork for male fertility preservation.…”

Section: Discussionmentioning

confidence: 65%

YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia

Guo,

Li,

et al. 2023

Biology of Reproduction

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Genomic integrity is critical for sexual reproduction, ensuring correct transmission of parental genetic information to the descendant. To preserve genomic integrity, germ cells have evolved multiple DNA repair mechanisms, together termed DNA damage response. RNA N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotic cells that plays important roles in DNA damage response, and YTHDF2 is a well-acknowledged m6A reader protein regulating the mRNA decay and stress response. Despite this, the correlation between YTHDF2 and DNA damage response in germ cells, if any, remains enigmatic. Here, by employing a Ythdf2-conditional knockout (cKO) mouse model as well as a Ythdf2-null GC-1 mouse spermatogonial cell line, we explored the role and the underlying mechanism for YTHDF2 in spermatogonial DNA damage response. We identified that despite no evident testicular morphological abnormalities under the normal circumstance, conditional mutation of Ythdf2 in adult male mice sensitized germ cells, including spermatogonia, to etoposide-induced DNA damage. Consistently, Ythdf2-KO GC-1 cells displayed the increased sensitivity and apoptosis in response to DNA damage, accompanied by the decreased SETDB1 (a histone methyltransferase) and H3K9me3 levels. Setdb1 knockdown in GC-1 cells generated the similar phenotype, but its overexpression in Ythdf2-null GC-1 cells alleviated the sensitivity and apoptosis in response to DNA damage. Taken together, these results demonstrate that the m6A reader YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia, which provides novel insights into the mechanisms underlying spermatogonial genome integrity maintenance and therefore contributes to safe reproduction.

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Section: Discussionmentioning

confidence: 65%

YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia

Guo,

Li,

et al. 2023

Biology of Reproduction

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“…The dormant state of spermatozoa with regards to metabolism and transcription should result in fewer DSBs, as metabolic stress and transcription are well-accepted causes of DNA damage ( Ui et al, 2020 ). However, mature spermatozoa are also characterized by the absence of active NHEJ, which is likely due to their genomic structure and the absence of certain relevant factors, although the mechanisms are still under scrutiny ( Talibova et al, 2022 ). To investigate the influence of the absent NHEJ activity on the characteristic DSB landscape of the sperm, we inhibited NHEJ activity in a somatic cell model.…”

Section: Resultsmentioning

confidence: 99%

DSB profiles in human spermatozoa highlight the role of TMEJ in the male germline

Scheuren,

Möhner,

Müller

et al. 2024

Front. Genet.

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The male mammalian germline is characterized by substantial chromatin remodeling associated with the transition from histones to protamines during spermatogenesis, followed by the reversal to nucleohistones in the male pronucleus preceding the zygotic genome activation. Both transitions are associated with the extensive formation of DNA double-strand breaks (DSBs), requiring an estimated 5 to 10 million transient DSBs per spermatozoa. Additionally, the high transcription rate in early stages of spermatogenesis leads to transcription-coupled damage preceding meiotic homologous recombination, potentially further contributing to the DSB landscape in mature spermatozoa. Once meiosis is completed, spermatozoa remain haploid and therefore cannot rely on error-free homologous recombination, but instead depend on error-prone classical non-homologous end joining (cNHEJ). This DNA damage/repair-scenario is proposed to be one of the main causes of the observed paternal mutation propensity in human evolution. Recent studies have shown that DSBs in the male pronucleus are repaired by maternally provided Polθ in Caenorhabditis elegans through Polθ-mediated end joining (TMEJ). Additionally, population genetic datasets have revealed a preponderance of TMEJ signatures associated with human variation. Since these signatures are the result of the combined effect of TMEJ and DSB formation in spermatozoa and male pronuclei, we used a BLISS-based protocol to analyze recurrent DSBs in mature human sperm heads as a proxy of the male pronucleus before zygotic chromatin remodeling. The DSBs were found to be enriched in (YR)n short tandem repeats and in evolutionarily young SINEs, reminiscent to patterns observed in murine spermatids, indicating evolutionary hotspots of recurrent DSB formation in mammalian spermatozoa. Additionally, we detected a similar DSB pattern in diploid human IMR90 cells when cNHEJ was selectively inhibited, indicating the significant impact of absent cNHEJ on the sperm DSB landscape. Strikingly, regions associated with most retained histones, and therefore less condensed chromatin, were not strongly enriched with recurrent DSBs. In contrast, the fraction of retained H3K27me3 in the mature spermatozoa displayed a strong association with recurrent DSBs. DSBs in H3K27me3 are associated with a preference for TMEJ over cNHEJ during repair. We hypothesize that the retained H3K27me3 may trigger transgenerational DNA repair by priming maternal Polθ to these regions.

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“…The male germ cells encounter DNA damage deriving from a number of exogenous and endogenous risk factors for infertility insults ( 27 - 30 ) which have different mechanisms during the process of spermatogenesis, including defective chromatin packaging, testicular apoptosis and seminal oxidative stress (shown in Figure 4 ). Meanwhile, due to a possibly dysfunctional repertoire of repair mechanisms, they do not get correctly repaired in a short time to maintain genomic integrity, which ultimately leads to high SDF ( 31 ). Studies have shown that excessive ROS and/or impaired antioxidant defense of the reproductive system production can induce DNA damage, impair genome stability during sperm transport throughout the male genital tract, and potentially impact pregnancy outcomes.…”

Section: Discussionmentioning

confidence: 99%

Outcomes comparison of testicular versus ejaculated sperm for intracytoplasmic sperm injection in infertile men with high DNA fragmentation: updated systematic review and meta-analysis

Zhao,

Jiang,

Zheng

et al. 2023

Transl Androl Urol

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Background The testicular sperm instead of ejaculated sperm for intracytoplasmic sperm injection (ICSI) in infertile men with high sperm DNA fragmentation (SDF) is a controversial topic. This updated systematic review and meta-analysis aims to evaluate whether couples with high level of SDF will benefit more from intracytoplasmic sperm injection with testicular sperm (Testi-ICSI) as compared to intracytoplasmic sperm injection with ejaculated sperm (Ejac-ICSI). Methods A systematic search was conducted according to PRISMA guidelines, using PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL), encompassing studies from the earliest record until May 2022. We included studies analyzing comparative pregnancy outcomes of testicular versus ejaculated sperm for ICSI in infertile men with high DNA fragmentation. The risks of bias and certainty of evidence were assessed using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, respectively. Results Eleven studies were included. Meta-analysis showed that SDF levels revealed a significant difference association [odds ratio (OR) =−25.81; 95% confidence interval (CI): −34.82, −16.81; I 2 =94%; P<0.00001] between testicular and ejaculated sperm. Compared with Ejac-ICSI, a non-significant tendency was observed for fertilization rates (FRs) in the Testi-ICSI group (OR =0.87; 95% CI: 0.67, 1.12; I 2 =81%; P=0.28). However, there was significant difference pointing to better outcomes for Testi-ICSI in clinical pregnancy rates (CPRs) (OR =2.36; 95% CI: 1.71, 3.24; I 2 =0%; P<0.00001), live birth rates (LBRs) (OR =3.10; 95% CI: 2.13, 4.51; I 2 =4%; P<0.00001) and miscarriage rates (MRs) (OR =0.28; 95% CI: 0.13, 0.60; I 2 =0%; P=0.001). Conclusions Results of this updated meta-analysis reveal that SDF rates are lower in testicular sperm than in ejaculated sperm and that Testi-ICSI is correlated with better clinical outcomes, including higher CPRs, higher LBRs, and lower MRs in infertile males with high SDF levels. Nevertheless, with the overall low to moderate quality of the studies, further well-designed controlled studies are required.

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DNA double-strand break repair in male germ cells during spermatogenesis and its association with male infertility development

Cited by 19 publications

References 139 publications

YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia

YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia

DSB profiles in human spermatozoa highlight the role of TMEJ in the male germline

Outcomes comparison of testicular versus ejaculated sperm for intracytoplasmic sperm injection in infertile men with high DNA fragmentation: updated systematic review and meta-analysis

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