**5.1 Incomplete DNA repair**

314 DNA Repair

NHEJ) and the alternative (or "back-up") pathway (referred to as B-NHEJ), which is also known as microhomology-mediated end-joining (MMEJ) (Ciccia and Elledge, 2010; West, 2003). Therefore, we will discuss known somatic DNA repair pathways and their potential

Given the haploid character spermatids, HR could not take place as sister chromatids or homologous chromosomes are not available for recombination. Considering that HR precisely restores the genomic sequence of the broken DNA ends by utilizing sister chromatids as template for DNA repair, HR usually occurs in late S2 and G phase of the cycle in mammals (Kass and Jasin, 2010), whereas spermatids are considered to be in a G1 like phase (Ahmed et al., 2010). Upon resection at DNA breaks by the MRN complex, two different pathways are usually possible: HR or SSA (Wold, 1997). The SSA pathway could use repetitive DNA sequences to promote the DNA repair of DSBs in spermatids (Hartlerode and Scully, 2009; Motycka et al., 2004). This pathway is known to introduce errors such as deletions, insertions and even be a substrate for chromosomal translocations (Griffin and Thacker, 2004). There is currently no evidence that spermatids use SSA rather than NHEJ to repair DSBs, but some key proteins of this pathway, although also part of the NER pathway (see Table 1 and Table 2), are present during spermiogenesis including

role in spermatids when supported by published data.

**4.3.1 Homologous recombination and single-strand annealing** 

ERCC1 (Hsia et al., 2003; Paul et al., 2007) as well as XPF (Shannon, 1999).

Homologous recombination (HR)

Single strand annealing (SSA)

Non-homologous endjoining DNA PK dependant (D-NHEJ)

Alternative nonhomologous end joining (B-NHEJ)

**4.3.2 Non-homologous end joining** 

**DNA repair pathways Implicated proteins Typical error** 

BRCA1/2, Rad51,

ERCC1, ERCC4 (XPF), Rad52

DNA PKcs, Ku70, ARTEMIS, XRCC4, LIG4, XLF (NHEJ1)

PARP, XRCC1, LIG3

Table 2. DNA double-strand break repair pathways and their typical error. (+) Occasional,

Besides SSA, B-NHEJ and D-NHEJ are potentially available for the repair of double-strand breaks during spermiogenesis (Leduc et al., 2008a; Leduc et al., 2008b). In somatic cells, NHEJ pathways promote the religation of DSBs, introducing small insertions and deletions. NHEJ pathways operates throughout the cell cycle but are most active during G1 phase

(++) frequent (Ciccia and Elledge, 2010; Griffin and Thacker, 2004).

XRCC2, LIG1, RPA Error free

Indels (++) Chromosomal translocation (++)

Indels (+) Chromosomal translocation (+)

Indels (+) Chromosomal translocation (+)

High level of sperm DNA fragmentation, sperm DNA damages and chromatin alterations decrease pregnancy rates in natural fertilization, intrauterine insemination and *in vitro* fertilization (Bungum et al., 2007; Duran, 2002; Evenson et al., 1999; Evenson and Wixon, 2006; Spano et al., 2000; Zini, 2011). Moreover, pregnancy loss following *in vitro* fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments has also been attributed to poor sperm DNA integrity (Zini et al., 2008). Although sperm DNA fragmentation is more frequent in infertile men, sperm of fertile men display DNA fragmentation but to a lesser extent (Bellver et al., 2010; Brahem et al., 2011; Perrin et al., 2009; Rybar et al., 2009; Venkatesh et al., 2011; Watanabe et al., 2011). After fertilization, the oocyte can efficiently repair some paternal DNA damages (Brandriff and Pedersen, 1981; Marchetti et al., 2007), but in the case of highly damaged sperm DNA, this could exceed the DNA repair capacity of the oocyte leading to some genetic aberrations, developmental arrest or pregnancy loss.
