**8. References**

420 DNA Repair

Consisting with that, mutations in checkpoint genes, such as Mec1, Ddc2, Rad9, Rad17, Rad24, or Rad53, produce repeat instabilities by a CAG~70, including both expansion and contraction instabilities. These suggested that DNA structure formed by long CAG repeats activated checkpoints in eukaryotes (Lahiri et al., 2004; Sundararajan & Freudenreich, 2011). Similarly, a CAG175 repeat on plasmids can also be recognized as ''DNA damage'' in *E. coli*,

Surprisingly, it was found that even those shorter CAG repeats (containing 13–20 triplets) can also intrigue DNA damage checkpoint. By which repeats expansion can be prevented when the repeats formed non-B structures, suggesting that cells have endowed the checkpoint mechanism of responding to non-B DNA structure formation (Razidlo &

Another example as intriguing cellular response for non-B DNA structure formation by derived structure processing is also found with human PKD1 gene. The 2.5-kb polypurine– polypyrimidine tract in intron 21 in human PKD1 gene potentially forms H-DNA structure, contributing to the high mutation rate of the PKD1 gene (Bacolla et al., 2001;Patel et al., 2004). A plasmid carrying this polypurine–polypyrimidine tract induced a stronge SOS response and severely delayed the host cell growth, resulting in a dramatic decrease in colony formation (Patel et al., 2004). However, the effect was largely reduced without UvrA (100-fold decrease in colony formation), and nearly vanished without UvrB or UvrC. These suggested the polypurine–polypyrimidine repeat sequence or the structure formed by the repeats per se was not involved in the effects, while the NER processing was essential

Apart from the nucleolytic activity, MRN / MRX can also play roles in activating the checkpoints as mentioned above (van den Bosch, et al., 2003; Sundararajan & Freudenreich, 2011). It was believed that a single stranded region in a non-B DNA structure forms ssDNA-RPA to the amount of triggering a checkpoint response (normally exceeds 300 bp). One way of Rad50-Mre11-Nbs1 (MRN) contributing to checkpoint response might be through Cut5 recruitment. Rad50-Mre11-Nbs1 (MRN) can be recruited to the single stranded region in the non-B DNA structure, and then participates in ATR checkpoint. Alternatively Rad50-Mre11- Nbs1 (MRN) can also secure DNA replication as implicated by its ortholog SbcCD in *E.coli*  (Darmon et al., 2007; Zahra et al., 2007). Indeed, the MRN / MRX complex has been co localized in the replication machinery. In this context, the resection role of MRN / MRX on DSB initiated recombination repair may be no more necessary as long as the checkpoints mechanism prevented the DSB formation by checkpoint proteins (Mimitou & Symington,

Non-B DNA structure forming sequences are potential triggers of DNA damage checkpoint responses mainly by inducing replication fork stalling and chromosomal breaks. Since the non-B DNA structures have specific DNA conformations at the damaged site, which may influence the checkpoint signaling, and the dynamics of checkpoint activation are likely to

Many lines of evidence suggest that unusual DNA structures can form *in vivo* and play significant roles in DNA metabolism, while they may also serve as a source for the

as witnessed by inducing SOS response (Majchrzak et al., 2006).

**6.5 Mre11-Rad50-Nbs1 (MRN)/ Mre11-Rad50-Xrs2 (MRX)** 

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**1. Introduction** 

**1.1 Recombinational repair**

multiple levels (Cox, 2007).

**1.2 Recombination mediator proteins**

**22** 

*USA* 

Sergey Korolev

*Saint Louis University School of Medicine* 

**ATP-Binding Cassette Properties of** 

**Recombination Mediator Protein RecF** 

*H*omologous *r*ecombination (HR) is essential for genetic diversity and genome stability. The conserved RecA-like recombinases promote pairing and consequent exchange of fragments between two homologous DNA molecules during conjugation in bacteria and meiotic recombination in eukaryotes. HR is a main DNA repair pathway particularly important in case of large-scale DNA damages, including chromosome or *d*ouble-*s*tranded (ds) *D*NA *b*reaks (DSBs) and long *s*ingle-*s*tranded (ss) DNA *g*aps (SSGs) (Cox, 1991; Kowalczykowski et al., 1994). The broken chain is paired with the intact DNA, which serves as a template for the synthesis of the damaged DNA. The same recombinases are also involved in the repair and origin-independent restart of stalled DNA replication, a frequently occurring event in

HR is initiated by the cooperative binding of RecA recombinase to ssDNA hundreds or thousands nucleotides long forming nucleoprotein filament, a so called presynaptic complex often designated as RecA\*. The presynaptic complex can bind homologous dsDNA and exchange a DNA strands. RecA\* has multiple activities beyond the strand invasion and exchange (Figure 1). Those include triggering DNA damage SOS response through stimulation of LexA autocleavage (Rehrauer et al., 1996) and activation of UmuD subunit of the error-prone DNA polymerase PolV important for translesion synthesis to bypass small-scale DNA errors (Jiang et al., 2009; Rajagopalan et al., 1992). RecA\* was also suggested to stabilize and maintain stalled replication fork during DNA repair (Courcelle et al., 1997). Consequently, RecA binding to DNA is regulated at

Transient ssDNA regions generated during replication are protected by ssDNA binding proteins like bacterial *ss*DNA *b*inding (SSB) protein and eukaryotic *r*eplication *p*rotein *A* (RPA), which prevent recombinase binding. Under DNA damage conditions, ubiquitous *r*ecombination *m*ediator *p*roteins (RMPs) overcome inhibitory effect of SSB and initiate presynaptic complex formation (Fig. 1)(Beernink and Morrical, 1999; Symington, 2002). RMPs are not directly involved in the repair of specific DNA damages, but they regulate initiation of multiple DNA repair pathways and damage response signaling cascades (Courcelle, 2005; Kowalczykowski, 2005; Lee and Paull, 2005; Moynahan et al., 2001;

every cell (Cox et al., 2000; Kowalczykowski, 2000; Kuzminov, 2001).


