XPF with mutations in its conserved nuclease domain is defective in DNA repair but functions in TRF2-mediated telomere shortening

Wu, Yili; Zacal, Natalie; Rainbow, Andrew J.; Zhu, Xu-Dong

doi:10.1016/j.dnarep.2006.09.005

Cited by 41 publications

(34 citation statements)

References 46 publications

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“…4B shows each median telomere length. In contrast to mTRF1 cond-KO, FLAG-mTRF1ϩ and mTRF1 cond-KO, FLAG-TIN2-cmTRF1ϩ ES cells, we found that mTRF1 cond-KO, FLAG-TRF2ϩ ES cells had a much shorter median telomere length (less than 20 kb) and remained this size during the culture period, in agreement with previous reports of TRF2-mediated telomere shortening (31)(32)(33) (Fig. 4A, lanes 7-9).…”

Section: Pot1-tpp1-independentsupporting

confidence: 81%

Distinct Roles of TRF1 in the Regulation of Telomere Structure and Lengthening

Okamoto

Iwano²,

Tachibana

et al. 2008

Journal of Biological Chemistry

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The telomere is a functional chromatin structure that consists of G-rich repetitive sequences and various associated proteins. Telomeres protect chromosomal ends from degradation, provide escape from the DNA damage response, and regulate telomere lengthening by telomerase. Multiple proteins that localize at telomeres form a complex called shelterin/telosome. One component, TRF1, is a double-stranded telomeric DNA binding protein. Inactivation of TRF1 disrupts telomeric localization of other shelterin components and induces chromosomal instability. Here, we examined how the telomeric localization of shelterin components is crucial for TRF1-mediated telomere-associated functions. We found that many of the mTRF1 deficient phenotypes, including chromosomal instability, growth defects, and dysfunctional telomere damage response, were suppressed by the telomere localization of shelterin components in the absence of functional mTRF1. However, abnormal telomere signals and telomere elongation phenotypes were either not rescued or only partially rescued, respectively. These data suggest that TRF1 regulates telomere length and function by at least two mechanisms; in one TRF1 acts through the recruiting/tethering of other shelterin components to telomeres, and in the other TRF1 seems to play a more direct role.The telomere is a chromosomal end structure comprised of G-rich tandem repeat sequences and various telomere localizing proteins. This structure prevents chromosome end degradation, escapes from the DNA damage response, and controls telomerase-mediated elongation (1, 2). In mammals, six telomere-localizing proteins, TRF1, TRF2, TIN2, RAP1, TPP1 (previously known as TINT1/PTOP/PIP1), and POT1 form a large complex termed the "shelterin/telosome," which is important for regulating telomeric structure and function (3-5). In addition, the 3Ј end of telomeric DNA is singlestranded, and this G-rich overhang is integrated into the double-stranded telomeric DNA region to form a loop structure called the t-loop; this loop prevents DNA damage recognition and telomerase access (5, 6).Previous studies have elucidated the role(s) of each shelterin component in telomere regulation as follows; TRF1 and TRF2 are telomeric double-stranded DNA-binding proteins. TRF1 is similar to TRF2 in structure and forms homodimers to bind telomeric DNA, but the major functions of these proteins are distinct (7,8). TRF1 negatively regulates telomerase-dependent elongation (9), and TRF1 deletion either in knock-out mouse ES cells or by small interfering RNA-mediated deletion revealed that TRF1 regulates telomeric localization of other shelterin components and maintains the functional telomere structure (3, 10 -13). On the other hand TRF2 is a telomere capping molecule, and deletion of TRF2 immediately induces end-to-end fusion, cell senescence, or cell death via the activation of telomere dysfunctional DNA damage responses (14 -16). These proteins are associated with TIN2, which contributes to the stabilization of telomeric localization of them (17, ...

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Section: Pot1-tpp1-independentsupporting

confidence: 81%

Distinct Roles of TRF1 in the Regulation of Telomere Structure and Lengthening

Okamoto

Iwano²,

Tachibana

et al. 2008

Journal of Biological Chemistry

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“…The skin phenotypes of K5TRF2 mice are also very similar to the skin pathologies present in patients with a defective telomerase pathway and the presence of short telomeres, such as in some cases of dyskerayosis congenita, aplastic anemia and pulmonary fibrosis (Mitchell et al, 1999;Vulliamy et al, 2001;Yamaguchi et al, 2005;Armanios et al, 2007;Tsakiri et al, 2007). In agreement with the short telomeres in these mice, a model has been proposed in which increased TRF2 expression results in higher XPF-ERCC1 activity at telomeres, leading to rapid XPF-dependent telomere degradation (Muñoz et al, 2005;Wu et al, 2007) and to the early onset of skinaging phenotypes (Muñoz et al, 2005). Concomitantly, decreased XPF activity at UV-induced lesions might lead to increased DNA damage and skin cancer (Muñoz et al, 2005;Muñoz et al, 2006; Blanco et al, 2007).…”

Section: Introductionsupporting

confidence: 58%

Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of the TRF2 telomeric protein on mouse epidermal stem cells

Stout

Blasco

2009

Disease Models &Amp; Mechanisms

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SUMMARYTRF2 is a telomere-binding protein involved in the protection of chromosome ends. Interestingly, TRF2 is overexpressed in a number of human cancers. Mice with increased TRF2 expression (K5TRF2 mice) display a severe skin phenotype including an increase in skin cancer and premature skin degeneration, which includes increased skin hyperpigmentation and skin dryness; these pathologies are concomitant with dramatic telomere shortening and increased chromosomal instability. Here, we show that K5TRF2 mice have a severe epidermal stem cell (ESC) dysfunction, which is reversed by abrogation of p53 in the absence of rescue of telomere length. Importantly, p53 deletion also rescues severe skin hyperpigmentation in these mice through regulation of alpha-melanocyte-stimulating hormone (α-MSH). In addition, skin carcinogenesis is accelerated in K5TRF2/p53 -/-mice owing to attenuated p21 induction, which enables cell proliferation to resume. Altogether, these results reveal the existence of a DNA damagedependent checkpoint that acts on ESCs with critically short telomeres and restricts skin proliferation, thereby increasing protection against skin cancer; however, the checkpoint also leads to premature skin aging phenotypes. Finally, the results described here are relevant to our understanding of the pathobiology of those human diseases that are characterized by the presence of critically short telomeres (hereafter referred to as 'telopathies'), such as dyskeratosis congenita which causes severe skin phenotypes including skin hyperpigmentation and skin cancer.

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“…116 Also, in human cells, overexpression of XPF led to a decrease in telomere length, in this case pointing to an effect in negative regulation of telomerase, 117 particularly dependent on TRF2. 118 Both observations could be explained by a role for XPF/ERCC1 on processing the overhang at normal telomeres, affecting both strands resulting from leading or lagging strand DNA synthesis. Further studies on the ERCC1/XPF complex will be informative in the possible interplay with other overhang processing activities.…”

Section: As Trf2mentioning

confidence: 99%