The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres

Méndez-Bermúdez, Aarón; Hidalgo‐Bravo, Alberto; Cotton, Victoria E.; Gravani, Athanasia; Jeyapalan, Jennie N.; Royle, Nicola J.

doi:10.1093/nar/gks862

Cited by 45 publications

(33 citation statements)

References 69 publications

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“…BLM, in conjunction with RAD51 can interact with TRF2 in ALT-activated cells to promote telomere elongation (Stavropoulos et al, 2002), while WRN is directly involved with telomeric recombination in the ALT pathway (Mendez-Bermudez et al, 2012). However, both WRN and BLM require a 3′ ssDNA tail to unwind a G-quadruplex (Mohaghegh et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

Telomeric Overhang Length Determines Structural Dynamics and Accessibility to Telomerase and ALT-Associated Proteins

et al. 2014

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The G-rich single stranded DNA at the 3′ end of human telomeres can self-fold into G-quaduplex (GQ). However, telomere lengthening by telomerase or the recombination-based alternative lengthening of telomere (ALT) mechanism requires protein loading on the overhang. Using single molecule fluorescence spectroscopy we discovered that lengthening the telomeric overhang also increased the rate of dynamic exchanges between structural conformations. Overhangs with five to seven TTAGGG repeats, compared to four repeats, showed much greater dynamics and accessibility to telomerase binding and activity, and loading of the ALT-associated proteins RAD51, WRN and BLM. Although the eight repeats are highly dynamic, they can fold into two GQs, which limited protein accessibility. In contrast, the telomere-specific protein, POT1 is unique in that it binds independently of repeat number. Our results suggest that the telomeric overhang length and dynamics may contribute to the regulation of telomere extension via telomerase action and the ALT mechanism.

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Section: Resultsmentioning

confidence: 99%

Telomeric Overhang Length Determines Structural Dynamics and Accessibility to Telomerase and ALT-Associated Proteins

et al. 2014

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“…Besides recurrent gain/ amplification of the established colorectal cancer gene MYC, recurrent regions of deletion in nonhypermutated cases included the candidate cancer genes PARK2 and WRN. WRN has important roles in homologous recombination repair, MUTYH-mediated repair of oxidative DNA damage, and telomeric recombination (34)(35)(36), and WRN germline mutations are associated with chromosomal instability and cancer predisposition (37). PARK2 deletion has been previously reported in sporadic colorectal cancer, and Park2 deficiency shown to accelerate intestinal adenoma development in Apc mutant mice (38).…”

Section: Discussionmentioning

confidence: 99%

Colorectal Cancer Cell Lines Are Representative Models of the Main Molecular Subtypes of Primary Cancer

et al. 2014

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Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ϵ proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses. Cancer Res; 74(12); 3238–47. ©2014 AACR.

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“…Telomere deprotection, specifically, down-regulation of TERF2, may also contribute to activation of “alternative telomere lengthening” (ALT) (Kamranvar et al, 2013), a recombination-based lengthening mechanism that does not involve telomerase and is believed to occur in differentiated cells (Neumann et al, 2013). Urinary arsenic was also positively asssociated with expession of MRE11A, a gene involved in ALT as well as homologous recombination (Escoffier et al, 2005) and WRN, which codes for a helicase protein that is involved in replication of telomereic DNA (including ALT) (Bhattacharyya et al, 2010) and prevention of telomere dysfunction (Crabbe et al, 2004; Eller et al, 2006; Mendez-Bermudez et al, 2012). Expression of WRN was modified significantly by the efficiency of arsenic metablism, suggesting an interaction between arsenic and metabolism efficiency.…”

Section: Discussionmentioning

confidence: 99%

Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals

Gao

Roy

Lin

et al. 2015

Environmental Research

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Background Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. Methods We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1,799 individuals. Association between arsenic exposure and a qPCR-based telomere length was assessed among 167 individuals. Results Urinary arsenic was possitively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P < 0.00035, Bonferroni correction threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction = 0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). Discussion Our findings suggest that arsenic’s carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes.

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The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres

Cited by 45 publications

References 69 publications

Telomeric Overhang Length Determines Structural Dynamics and Accessibility to Telomerase and ALT-Associated Proteins

Telomeric Overhang Length Determines Structural Dynamics and Accessibility to Telomerase and ALT-Associated Proteins

Colorectal Cancer Cell Lines Are Representative Models of the Main Molecular Subtypes of Primary Cancer

Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals

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