Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A

Liu, Yiyong; Wang, Youjie; Rusiñol, Antonio E.; Sinensky, Michael; Liu, Ji; Shell, Steven M.; Zou, Yue

doi:10.1096/fj.07-8598com

Cited by 99 publications

(133 citation statements)

References 46 publications

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“…Because the function of DNA repair proteins and chromatinremodeling enzymes is dependent on their proper positioning on the nuclear matrix (32), we hypothesize that the extra 18 amino acids at the carboxyl terminus of unprocessed prelamin A severely reduces the binding of Mof on the nuclear matrix and disrupts its histone acetylation functions. Intriguingly, apart from Mof, progerin expression has been shown to contribute to the mislocalization of ATR, SKIP, and XPA and to the degradation of NURD chromatin-remodeling complex subunits (16,29,(33)(34)(35). The critical question that arises from these reports is why unprocessed lamin A expression elicits such pleiotropic outcomes.…”

Section: Discussionmentioning

confidence: 99%

Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice

Krishnan

Chow

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

205

156

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Specific point mutations in lamin A gene have been shown to accelerate aging in humans and mice. Particularly, a de novo mutation at G608G position impairs lamin A processing to produce the mutant protein progerin, which causes the Hutchinson Gilford progeria syndrome. The premature aging phenotype of Hutchinson Gilford progeria syndrome is largely recapitulated in mice deficient for the lamin A-processing enzyme, Zmpste24. We have previously reported that Zmpste24 deficiency results in genomic instability and early cellular senescence due to the delayed recruitment of repair proteins to sites of DNA damage. Here, we further investigate the molecular mechanism underlying delayed DNA damage response and identify a histone acetylation defect in Zmpste24 −/− mice. Specifically, histone H4 was hypoacetylated at a lysine 16 residue (H4K16), and this defect was attributed to the reduced association of a histone acetyltransferase, Mof, to the nuclear matrix. Given the reversible nature of epigenetic changes, rescue experiments performed either by Mof overexpression or by histone deacetylase inhibition promoted repair protein recruitment to DNA damage sites and substantially ameliorated agingassociated phenotypes, both in vitro and in vivo. The life span of Zmpste24 −/− mice was also extended with the supplementation of a histone deacetylase inhibitor, sodium butyrate, to drinking water. Consistent with recent data showing age-dependent buildup of unprocessable lamin A in physiological aging, aged wild-type mice also showed hypoacetylation of H4K16. The above results shed light on how chromatin modifications regulate the DNA damage response and suggest that the reversal of epigenetic marks could make an attractive therapeutic target against laminopathybased progeroid pathologies. E ukaryotic cells are equipped with a surveillance machinery to orchestrate the rapid detection and repair of DNA damage. When DNA damage occurs, chromatin surrounding the doublestrand breaks (DSBs) is altered and histones are modified to facilitate access for repair proteins (1). As a rapid response to DSB induction, the histone H2A variant, H2AX, is phosphorylated at Ser139 (γ-H2AX), which in turn interacts with MDC1, a DSB repair mediator, to facilitate the further recruitment of DNA repair proteins, such as 53BP1 and BRCA1 (2-4). Interestingly, γ-H2AX accumulation has been documented both in human senescent cells and in the fibroblasts of aged mice and primates (5-8). It has been proposed that these age-associated γ-H2AX foci contain nonrepairable DSBs and may have a role in initiating aging, especially because DSBs are very toxic and are one of the most lethal forms of DNA damage. Direct evidence for nonrepairable DNA damage as an inducer of premature aging has been obtained from mouse models that lack DNA repair proteins, such as ATM, Ku70, Ku80, DNA ligase IV, and Ercc1, as well as from humans with premature aging syndromes (9, 10). Together, these studies support the idea that the inability to recruit repair proteins to sites of DNA les...

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Section: Discussionmentioning

confidence: 99%

Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice

Krishnan

Chow

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

205

156

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“…Recently, it has been demonstrated that the Xeroderma Pigmentosum group A (XPA) protein, an unique nucleotide excision repair protein, localizes to or near DSBs in HGPS and RD cells. 33 The mislocalization of XPA to the DSBs sites inhibits their repair, thus suggesting a role of XPA in the genome instability observed in progeria disorders arising from genetic defects in the prelamin A maturation. 33 Alternatively, the persistence of unresolved repair foci might reflect the presence of stalled replication complexes at sites of DNA damage, either caused by defects in the repair machinery or by aberrant progression due to the altered lamin network.…”

Section: Discussionmentioning

confidence: 99%

“…33 The mislocalization of XPA to the DSBs sites inhibits their repair, thus suggesting a role of XPA in the genome instability observed in progeria disorders arising from genetic defects in the prelamin A maturation. 33 Alternatively, the persistence of unresolved repair foci might reflect the presence of stalled replication complexes at sites of DNA damage, either caused by defects in the repair machinery or by aberrant progression due to the altered lamin network. 27 The response to DNA damage involves the activation of complex checkpoint signalling pathways that delay the cell cycle progression and permit the repair of the lesion.…”

Section: Discussionmentioning

confidence: 99%

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

Masi¹,

D’Apice²,

Ricordy³

et al. 2008

Cell Cycle

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Mandibuloacral dysplasia type A (MADA; OMIM # 248370) is a premature ageing disease caused by the homozygous R527H mutation in the LMNA gene. At the cellular level, MADA is characterized by unprocessed prelamin A accumulation, nuclear architecture alterations, chromatin defects and increased incidence of apoptosis. In some progeroid laminopathies (e.g., HGPS) it has been demonstrated that such biochemical and morphological alterations are strongly linked with genomic instability. To test this also in MADA fibroblasts, their response to the ionising radiationinduced damage was analysed. We observed that their ability to repair the damage was significantly impaired, as demonstrated by the increased chromosome damage and the higher percentage of residual γ-H2AX foci, corresponding to unrepaired DNA-damage sites. Moreover, MADA fibroblasts showed a markedly reduced phosphorylation of p53 at Ser15(S15) and a lower induction of p53 and CDKN1A proteins after irradiation, compared to the control cell line. Upon irradiation, we also detected differences in the expression of some p53 downstream target genes. In addition, MADA cells showed partial defects in the checkpoint response, particularly in G 1 /S transition.Our results indicate that accumulation of the lamin A precursor protein determines a defect in DNA damage response after X-ray exposure, supporting a crucial role of lamin A in regulating DNA repair process and cell cycle control.

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“…Accumulation of progerin and farnesylated prelamin A has been correlated with defective DNA repair mechanisms and genomic instability [93][94][95]. Progerin binds to DNA-dependent protein kinase catalytic subunit, which functions in genomic stability [96].…”

Section: Pathophysiology and Potential Treatmentsmentioning

confidence: 99%

Nuclear lamins and laminopathies

Worman¹

2011

The Journal of Pathology

342

313

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Nuclear lamins are intermediate filament proteins that polymerize to form the nuclear lamina on the inner aspect of the inner nuclear membrane. Long known to be essential for maintaining nuclear structure and disassembling/reassembling during mitosis in metazoans, research over the past dozen years has shown that mutations in genes encoding nuclear lamins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, often referred to as laminopathies. Lamins are expressed in all mammalian somatic cells but mutations in their genes lead to relatively tissue-selective disease phenotypes in most cases. While mutations causing laminopathies have been shown to produce abnormalities in nuclear morphology, how these disease-causing mutations or resultant alterations in nuclear structure lead to pathology is only starting to be understood. Despite the incomplete understanding of pathogenic mechanisms underlying the laminopathies, basic research in cellular and small animal models has produced promising leads for treatments of these rare diseases.

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Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A

Cited by 99 publications

References 46 publications

Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice

Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

Nuclear lamins and laminopathies

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