interacts physically with the Mre11-RAD50-NBS1 complex, which also functions in HR for DSB processing (Cheng et al 2004). Base excision repair Oxidative DNA lesions are repaired primarily by base excision repair (BER), and the accumulation of oxidative products and the resulting phenotypic changes have been implicated in the aging process (Beckman et al 1998). In general, BER can be divided into short patch repair and long patch repair. WRN has been shown to physically interacts with polβ and participate in short patch BER (Harrigan et al 2003). The active WRN helicase domain stimulates polβ strand displacement DNA synthesis at a nick on a BER substrate (Harrigan et al 2003). In addition, it has been shown to interact physically and/or functionally with several replication proteins which participate in long patch BER, including PCNA, RPA, polδ, and FEN-1 (Shen et al 1998; Brosh et al 1999, 2002; Kamath-Loeb et al 2001). PCNA is part of a sliding clamp which forms a ring which maintains the connection between polymerase and its DNA template, allowing uninterrupted synthesis. WRN has been shown to directly interact with PCNA in vitro, suggesting a unique role for WRN in DNA synthesis (Huang et al 2000). WRN stimulates FEN-1 ﬂap cleavage (Brosh et al 2001c, 2002) and nucleotide incorporation by polδ (Kamath-Loeb et al 2000, 2001). RPA stimulates WRN helicase unwinding of long substrates (Shen et al 1998; Brosh et al 1999) and the poly(ADP-ribosyl)ation state of PARP-1 regulates WRN helicase and exonuclease activities (von Kobbe et al 2004). PARP-1 binds strongly to strand breaks and acts in the DNA damage surveillance network, partly by ribosylating a variety of nuclear proteins in response to DNA damage. DNA recombination Cellular DNA recombination can occur physiologically during meiotic DNA replication and V(D)J recombination, or can be induced by DNA damaging agents. Some reports define a physiological role for WRN RecQ helicase in recombination via RAD51-dependent HR (Prince et al 2001; Saintigny et al 2002). WRN and BLM colocalize to DNA damage-induced RAD51 foci, implicated in HR (Bischof et al 2001; Sakamoto et al 2001; Wu et al 2001; Saintigny et al 2002; Von Kobbe et al 2002; Wu and Hickson 2003; Spillare et al 2006). The WRN and BLM helicase activities are possible in a synergistic manner to intermediate DNA recombination, since a coimmunoprecipitation and colocal- ization study showed that the exonuclease domain of WRN Clinical Interventions in Aging 2008:3(3) Werner’s and Hutchinson-Gilford progeria syndromes interacts with BLM (von Kobbe and Bohr 2002). In addition, a biochemical study showed that WRN interacts with the homologous recombination mediator protein RAD52, and that WRN and RAD52 form a complex, should be a gen- eral response to replication forks arrested by DNA damage (Baynton et al 2003). WRN interacts physically and functionally with the MRN complex via NBS1 and they colocalize in response to ionizing radiation or mitomycin C treatment (Cheng et al 2004). WS cells display a deﬁciency in resolving DNA recombination intermediates which contributes to DNA damage hypersen- sitivity, limited cell growth, and genomic instability (Prince et al 2001). The generation of viable mitotic recombinant progeny was rescued by the expression of WRN, which also improved WS cell survival after DNA damage (Saintigny et al 2002). These results deﬁne a physiological role for the WRN RecQ helicase protein in RAD51-dependent HR and identify a mechanistic link between defective recombina- tion resolution and limited cell division potential, DNA damage hypersensitivity, and genetic instability in human somatic cells (Saintigny et al 2002). WRN also colocal- izes with RAD51 and RPA in response to DNA damaging agents (Constantinou et al 2000; Sakamoto et al 2001), and both WRN and BLM interact with RPA (Brosh et al 1999, 2000). Telomere maintenance Telomeres are specialized nucleoprotein structures con- sisting of G-rich repetitive sequences that cap the ends of eukaryotic chromosomes and are crucial for the maintenance of chromosomal integrity and cell viability (McClintock et al 1941). They are maintained by the enzyme telomerase, which consists of an essential telomerase RNA component (TERC), which serves as a template for the addition of telomere repeats, and a protein component, the telomerase reverse transcriptase catalytic subunit (TERT). Telomere shorten- ing eventually results in diverse pathophysiological conse- quences, primarily through accelerated telomere erosion, and triggers entry into premature senescence (Wright and Shay 1992; Blasco 2002; Chang et al 2004; Du et al 2004). Defects in telomere structure can initiate a DNA damage response and may lead to telomeric end fusions and chromosome breakage if not properly repaired (De Lange 2002). Biochemical and cellular evidence suggest that WRN may dissociate secondary structures at the telomere to allow replication, repair, and telomerase activity at the telomere end (Opresko et al 2003). Under normal conditions, WRN associates with telomeres in S phase to prevent loss of 435