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Last update 08 May 2025

Xeroderma Pigmentosum, Variant Type

Last update 08 May 2025

Basic Info

Synonyms

PHOTOSENSITIVITY WITH DEFECTIVE DNA SYNTHESIS, Photosensitivity with defective DNA synthesis, XERODERMA PIGMENTOSUM WITH NORMAL DNA REPAIR RATES

+ [7]

Introduction

A type of xeroderma pigmentosum resulting from mutation(s) in the POLH gene, encoding DNA polymerase eta. This form of the disease is characterized by normal DNA excision repair, but defective post-replication repair of DNA at UV-damaged sites.

Drugs associated with Xeroderma Pigmentosum, Variant Type

D-501036

Target

Chk1 x POLH

Mechanism

Chk1 inhibitors [+1]

Active Org.-

Originator Org.

National Health Research Institutes

Active Indication-

Inactive Indication

Neoplasms [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Xeroderma Pigmentosum, Variant Type

100 Translational Medicine associated with Xeroderma Pigmentosum, Variant Type

0 Patents (Medical) associated with Xeroderma Pigmentosum, Variant Type

Literatures (Medical) associated with Xeroderma Pigmentosum, Variant Type

18 Aug 2023·Carcinogenesis

Mutational signatures and increased retrotransposon insertions in xeroderma pigmentosum variant skin tumors.

Article

Author: de Souza, Tiago A ; Saldiva, Paulo ; Sotto, Mirian N ; Vilar, Juliana B ; Miller, Thiago L A ; Buzzo, José L ; Menck, Carlos F M ; Buzatto, Vanessa C ; Corradi, Camila ; de Oliveira, Jocelânio W ; Sarasin, Alain ; Munford, Veridiana ; Chaibub, Sulamita C W ; De Vecchi, Rodrigo ; Galante, Pedro A F ; Castro, Ligia P ; Orpinelli, Fernanda

Xeroderma pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk of developing cutaneous neoplasms in sunlight-exposed regions. These cells are deficient in the translesion synthesis (TLS) DNA polymerase eta, responsible for bypassing different types of DNA lesions. From the exome sequencing of 11 skin tumors of a genetic XP-V patients' cluster, classical mutational signatures related to sunlight exposure, such as C>T transitions targeted to pyrimidine dimers, were identified. However, basal cell carcinomas also showed distinct C>A mutation spectra reflecting a mutational signature possibly related to sunlight-induced oxidative stress. Moreover, four samples carry different mutational signatures, with C>A mutations associated with tobacco chewing or smoking usage. Thus, XP-V patients should be warned of the risk of these habits. Surprisingly, higher levels of retrotransposon somatic insertions were also detected when the tumors were compared with non-XP skin tumors, revealing other possible causes for XP-V tumors and novel functions for the TLS polymerase eta in suppressing retrotransposition. Finally, the expected high mutation burden found in most of these tumors renders these XP patients good candidates for checkpoint blockade immunotherapy.

11 Jan 2023·NAR Cancer

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

Article

Author: Zhang, Xingyuan ; Sciandra, Carly ; Wu, Di ; Vaziri, Cyrus ; Anand, Jay ; Zhou, Pei ; Chiou, Lilly ; Hong, Jiyong

AbstractDNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The ‘Y-family’ trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.

23 Sep 2022·Nucleic Acids Research

Changes in the architecture and abundance of replication intermediates delineate the chronology of DNA damage tolerance pathways at UV-stalled replication forks in human cells

Article

Author: Dupaigne, Pauline ; Benureau, Yann ; Kannouche, Patricia L ; Despras, Emmanuelle ; Baconnais, Sonia ; Pouvelle, Caroline ; Le Cam, Eric ; Moreira Tavares, Eliana ; Mazón, Gerard

AbstractDNA lesions in S phase threaten genome stability. The DNA damage tolerance (DDT) pathways overcome these obstacles and allow completion of DNA synthesis by the use of specialised translesion (TLS) DNA polymerases or through recombination-related processes. However, how these mechanisms coordinate with each other and with bulk replication remains elusive. To address these issues, we monitored the variation of replication intermediate architecture in response to ultraviolet irradiation using transmission electron microscopy. We show that the TLS polymerase η, able to accurately bypass the major UV lesion and mutated in the skin cancer-prone xeroderma pigmentosum variant (XPV) syndrome, acts at the replication fork to resolve uncoupling and prevent post-replicative gap accumulation. Repriming occurs as a compensatory mechanism when this on-the-fly mechanism cannot operate, and is therefore predominant in XPV cells. Interestingly, our data support a recombination-independent function of RAD51 at the replication fork to sustain repriming. Finally, we provide evidence for the post-replicative commitment of recombination in gap repair and for pioneering observations of in vivo recombination intermediates. Altogether, we propose a chronology of UV damage tolerance in human cells that highlights the key role of polη in shaping this response and ensuring the continuity of DNA synthesis.

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