Transition from a meiotic to a somatic-like DNA damage response during the pachytene stage in mouse meiosis

Abstract

Homologous recombination (HR) is the principal mechanism of DNA repair acting during meiosis and is fundamental for the segregation of chromosomes and the increase of genetic diversity. Nevertheless, non-homologous end joining (NHEJ) mechanisms can also act during meiosis, mainly in response to exogenously-induced DNA damage in late stages of first meiotic prophase. In order to better understand the relationship between these two repair pathways, we studied the response to DNA damage during male mouse meiosis after gamma radiation. We clearly discerned two types of responses immediately after treatment. From leptotene to early pachytene, exogenous damage triggered the massive presence of γH2AX throughout the nucleus, which was associated with DNA repair mediated by HR components (DMC1 and RAD51). This early pathway finished with the sequential removal of DMC1 and RAD51 and was no longer inducible at mid pachytene. However, from mid-pachytene to diplotene, γH2AX appeared as large discrete foci. This late repair pattern was mediated initially by NHEJ, involving Ku70 and XRCC4, which were constitutively present, and 53BP1, which appeared at sites of damage soon after irradiation. Nevertheless, 24 hours after irradiation, a HR pathway involving RAD51 but not DMC1 mostly replaced NHEJ. Additionally, we observed the occurrence of synaptonemal complex bridges between bivalents, most likely representing chromosome translocation events that may involve DMC1, RAD51 or 53BP1. Our results reinforce the idea that the early “meiotic” repair pathway that acts by default at the beginning of meiosis is replaced from mid-pachytene onwards by a “somatic-like” repair pattern. This shift might be important to resolve DNA damage (either endogenous or exogenous) that could not be repaired by the early meiotic mechanisms, for instance those in the sex chromosomes, which lack a homologous chromosome to repair with. This transition represents another layer of functional changes that occur in meiotic cells during mid pachytene, in addition to epigenetic reprograming, reactivation of transcription, changes in the gene expression profile and acquisition of competence to proceed to metaphase.

A meiosis-specific factor C19orf57/4930432K21Rik/BRME1 modulates localization of RAD51 and DMC1 recombinases to DSBs in mouse meiotic recombination

“…Further, it was previously shown that MEILB2/HSF2BP persisted in pahytene (Zhang et al, 2019). It was demonstrated that early meiotic repair pathway that acts by default at the beginning of meiotic prophase is replaced sequentially by non-homologous end joining (NHEJ) and somatic-like homologous recombination (HR) pathway involving RAD51 (Enguita-Marruedo et al, 2019). Although we do not yet know the biological relevance of the detectable MRM foci in late meiotic prophase, MRM may be involved in "somatic-like HR repair pathway" in that stage.…”

Signatures of replication timing, recombination and sex in the spectrum of rare variants on the human X chromosome and autosomes

“…One possibility is that the enrichment of C>G mutations stems from a switch in the repair machinery late in meiosis (78-80); DSBs still not repaired by this stage may be repaired by a more mitotic-like repair pathway, which could potentially be more mutagenic (80,81). Notably, the source of the C>G signature found by Jónsson et al, 2017 in specific autosomal regions could also be late repair; indeed, if these areas reflect damage, as the authors surmise, they may only undergo repair later in meiosis.…”

A Reporter Mouse forIn VivoDetection of DNA Damage in Embryonic Germ Cells

“…While repair of DSBs in meiosis occurs exclusively via HR pathway components, 53BP1 is associated primarily with the non-homologous end joining (NHEJ) DSB repair pathway. Therefore, its activity as a DSB responsive element may be down-regulated during early meiosis (Enguita-Marruedo et al, 2019), resulting in less 53BP1-based reporter foci detection in the female germ cells at this time.…”