Recent studies have demonstrated significant cross

Recent studies have demonstrated significant cross-talk between XRCC1 (a key player in IMR-1 excision repair (BER) and single strand break repair) and DDR [30], [31], [32]. ATM and DNA-PKcs are known to be involved in the phosphorylation of XRCC1 to promote BER [30], [31]. We have recently shown that XRCC1 is key predictive biomarker of platinum resistance in ovarian cancers [23]. In the current study we therefore explored if patient stratification could be achieved based on XRCC1, ATM, DNA-PKcs and ATR expression statuses in tumours. ATM+/XRCC1+, DNA-PK+/XRCC1+ and ATR+/XRCC1+ tumours had the worst survival compared to ATM-/XRCC1-, DNA-PK-/XRCC1- and ATR-/XRCC1- tumours in our study. However, a limitation of our study is that it is retrospective and involves a limited number of patients. Larger studies are required to confirm our findings. The recent success of PARP1 inhibitors (that block BER and SSBR) in germ-line BRCA deficient ovarian cancer [33], [34] provides evidence that targeting DNA repair is an important area for personalization of ovarian cancer therapy. Although the data in germ-line BRCA deficient tumours is promising, the search for such synthetic lethal relationships in the more common sporadic epithelial ovarian cancer remains an area of on-going investigation. In a recent pre-clinical study, we have demonstrated that ATM, DNA-PKcs and ATR inhibitors are synthetically lethal in XRCC1 deficient cancer cells [35], [36]. Taken together, our data suggests that XRCC1 based personalization using ATM, DNA-PKcs or ATR inhibitors may be feasible and this approach clearly warrants further investigation in vivo in sporadic epithelial ovarian cancers. The associations demonstrated herein between ATM, DNA-PKcs and cell cycle markers such as CDK1 and CDC25 are also consistent with the known roles of ATM and DNA-PKcs during cell cycle progression [37].
Conflicts of interest The following are the supplementary data related to this article.
Introduction Vertebrate telomeres are repetitive TTAGGG DNA sequences located at the ends of chromosomes, which protect the coding regions of DNA. In mammalian germline cells and ∼85% of cancers, telomere length is maintained by the dimeric ribonucleoprotein telomerase, which catalyzes the addition of TTAGGG repeats to counteract telomere shortening and cellular senescence (Shay and Bacchetti, 1997, Kim et al., 1994, Wenz et al., 2001). The minimal catalytic core of human telomerase consists of the telomerase reverse transcriptase protein (hTERT), telomerase RNA (hTR), and the protein dyskerin (Cohen et al., 2007). The differentiation of telomeres from broken chromosome ends is conferred by a family of six telomere-specific binding proteins collectively termed “shelterin” (de Lange, 2005). This complex consists of the double-stranded binding proteins TRF1 and TRF2, the single-stranded binding proteins POT1 and TPP1, the bridging protein TIN2 that links these two groups of proteins, and Rap1 (reviewed in Palm and de Lange, 2008). TRF1 protects the telomere and negatively regulates telomerase-mediated telomere lengthening (van Steensel and de Lange, 1997, Smogorzewska et al., 2000, Ancelin et al., 2002, Karlseder et al., 2002). TRF1 also facilitates the progression of the replication machinery; deletion of TRF1 increases replication fork stalling, leading to ATR kinase activation and a “fragile telomere” phenotype (Sfeir et al., 2009, Martínez et al., 2009). The TRF1-mediated repression of the ATR response requires recruitment of the shelterin components TIN2 and the TPP1/POT1 heterodimer (Zimmermann et al., 2014). TPP1 and POT1 also have roles in mediating telomere-length regulation. A surface on the N-terminal oligonucleotide/oligosaccharide-binding (OB) domain of TPP1 termed the TEL patch activates telomerase by stimulating telomerase processivity and providing a direct binding site for telomerase recruitment to telomeres; mutation of the TEL patch can lead to telomere shortening syndromes characterized by bone marrow failure (Abreu et al., 2010, Nandakumar et al., 2012, Zhong et al., 2012, Kocak et al., 2014, Guo et al., 2014, Dalby et al., 2015). Additionally, mutation analyses at sites independent of the TEL patch have implicated TPP1 as part of a telomere-length-dependent feedback loop that regulates telomere-length homeostasis (Sexton et al., 2014). A mutant form of POT1 that abrogates binding to single-stranded DNA (POT1ΔOB) deregulated telomere-length control (Loayza and De Lange, 2003), indicating that the DNA-binding capability of POT1 is vital as a negative regulator of telomere length. The impact of human POT1 on telomere length is complex, since both depletion and overexpression of POT1 lead to telomere lengthening (Ye et al., 2004, Veldman et al., 2004, Colgin et al., 2003, Armbruster et al., 2004). POT1 function as a positive or negative regulator of telomerase activity at the telomere depends on its position of binding relative to the DNA 3′ end and is also modulated by its binding partner, TPP1 (Zaug et al., 2005, Wang et al., 2007, Lei et al., 2005, Kelleher et al., 2005).