Continuous double-strand break induction and their differential processing sustain chiasma formation during Caenorhabditis elegans meiosis.

Faithful chromosome segregation into gametes depends on Spo11-induced DNA double-strand breaks (DSBs). These yield single-stranded 3' tails upon resection to promote crossovers (COs). While early Mre11-dependent end resection is the predominant pathway in most organisms, Exo1 or Dna2/BLM can also contribute to the efficient processing of meiotic DSBs. Although its enzymatic activity has been thoroughly dissected, the temporal dynamics underlying Spo11 activity have remained mostly elusive. We show that, in Caenorhabditis elegans, SPO-11-mediated DSB induction takes place throughout early meiotic prophase I until mid-late pachynema. We find that late DSBs are essential for CO formation and are preferentially processed by EXO-1 and DNA-2 in a redundant fashion. Further, EXO-1-DNA-2-mediated resection ensures completion of conservative DSB repair and discourages activation of KU-dependent end joining. Taken together, our data unveil important temporal aspects of DSB induction and identify previously unknown functional implications for EXO-1-DNA-2-mediated resection activity in C. elegans.

R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline.

Accumulation of DNA-RNA hybrids in the form of R-loops can result in replication-transcription conflict that leads to the formation of DNA double strand breaks (DSBs). Using null mutants for the two Caenorhabditis elegans genes encoding for RNaseH1 and RNaseH2, we identify novel effects of R-loop accumulation in the germline. R-loop accumulation leads, as expected, to replication stress, followed by the formation of DSBs. A subset of these DSBs are irreparable. However, unlike irreparable DSBs generated in other systems, which trigger permanent cell cycle arrest, germline irreparable DSBs are propagated to oocytes. Despite DNA damage checkpoint activation in the stem cell niche, the signaling cannot be sustained and nuclei with irreparable DNA damage progress into meiosis. Moreover, unlike other forms of DNA damage that increase germline apoptosis, R-loop-generated DSBs remain undetected by the apoptotic checkpoint. This coincides with attenuation of ATM/ATR signaling in mid-to-late meiotic prophase I. These data altogether indicate that in the germline, DSBs that are generated by R-loops can lead to irreparable DSBs that evade cellular machineries designed for damage recognition. These studies implicate germline R-loops as an especially dangerous driver of germline mutagenesis.

Postpartum sexual functioning and method of delivery: summary of the evidence.

Short-term postpartum sexual problems are highly prevalent, ranging from 22% to 86%; however, there are few studies that address how mode of delivery affects sexual functioning after childbirth. The objective of this study was to perform a systematic review of the literature on selected postpartum sexual function outcomes as affected by cesarean, assisted vaginal, and spontaneous vaginal delivery. We searched PubMed, CINAHL, and Cochrane databases from January 1990 to September 2003 and focused on mode of delivery and the most commonly reported sexual health outcomes, which included perineal pain, dyspareunia, resumption of intercourse, and self-reported perception of sexual health/sexual problems. The studies all showed increased risks of delay in resumption of intercourse, dyspareunia, sexual problems, or perineal pain associated with assisted vaginal delivery. Some studies showed no differences in sexual functioning between women with cesarean delivery and those with spontaneous vaginal delivery, whereas others reported less dyspareunia for women with cesarean delivery. A systematic review of the literature suggests an association between assisted vaginal delivery and some degree of sexual dysfunction. Reported associations between cesarean delivery and sexual dysfunction were inconsistent. Continued research is necessary to identify modifiable risk factors for sexual problems related to method of delivery.