Koichi sato, inger brandsma, sari e van rossumfikkert, nicole verkaik, anneke b oostra, josephine c dorsman, dik c van gent, puck knipscheer, roland kanaar, alex n zelensky, hsf2bp negatively regulates homologous recombination in dna interstrand crosslink repair, nucleic acids research, volume 48, issue 5, 18 march 2020, pages 24422456. Histone h2ax phosphorylation as a molecular pharmacological marker for dna interstrand crosslink cancer chemotherapy. Dna interstrand crosslinks icls are formed by bifunctional agents and covalently link two strands of a dna duplex. Moreover, icls can induce mutations and rearrangements of dna, possibly resulting in uncontrolled cell growth and tumor formation. Dna interstrand crosslinks icls are among the most toxic dna damages. Replication fork reversal during dna interstrand crosslink. Dna interstrand crosslinks, with emphasis on repair, cell. The fanconi anemia pathway promotes replicationdependent. Biallelic mutations of fancd2 and other components of the fanconi anemia fa pathway cause a disease characterized by bone marrow failure, cancer predisposition and a striking sensitivity to agents that induce crosslinks between the two complementary dna strands interstrand crosslinks icl. Dna interstrand crosslinks icls are lesions that covalently link opposing strands of the double helix. Disturbed this icl repair orchestration in s phase causes genome instability resulting a cancer prone disease, fanconi anemia. Dna crosslinking damage occurs when crosslinking agents covalently connect two nucleotide residues from the same dna strand intrastrand crosslink or from opposite strands interstrand crosslink icl.
Crosslink structure affects replicationindependent dna interstrand crosslink repair in mammalian cells. Mutations in fa proteins give rise to fanconi anemia, a cancer predisposition syndrome. Snm1bapollo in the dna damage response and telomere. The main repair pathway in escherichia coli involves the sequential action of nucleotide excision repair ner and recombinational repair. The role of adpribosylation in regulating dna interstrand.
In vertebrate cells, dna interstrand crosslink icl repair is coupled to dna replication and involves structurespecific endonucleases, translesion dna polymerases, recombinases, and numerous proteins mutated in the human disease fanconi anemia fa. Covalent dna protein crosslinks dpcs are induced by various compounds, which include widely used anticancer drugs, and are highly cytotoxic. However, cellular responses triggered by icls can cause resistance in tumor cells, limiting the efficacy of such treatment. Since the icl lesion affects both strands of the dna, the icl repair is not simple. Deficiency of dna repair nuclease ercc1xpf promotes.
Agents that induce icls were one of the earliest, and are still the most widely used, forms of chemotherapeutic drug. Interstrand crosslinks icls are highly toxic dna lesions that prevent transcription and replication by inhibiting dna strand separation. Icls are repaired during and outside s phase, and replicationindependent icl repair rir is critical to maintain genomic integrity and to allow transcription in nondividing or slowly dividing cells. Unrepaired icls often lead to cell death, a trait that is exploited in cancer chemotherapy by using icl inducing agents to kill cancer cells. Dna interstrand crosslinks icls are highly toxic lesions associated with cancer and degenerative diseases. Sensing and processing of dna interstrand crosslinks by. Fancd2 and ctip cooperate to repair dna interstrand crosslinks.
Dna interstrand crosslinks icls are toxic dna lesions whose repair occurs in the s phase of metazoans via an unknown mechanism. Fanconi anemia proteins, dna interstrand crosslink repair. Cancer treatments have been engineered using dna crosslinking agents to interact. Additionally, some compounds widely used in anticancer therapies, such as mitomycin c. So far, nucleotide excision repair ner, structurespecific endonucleases, translesion dna synthesis tls, homologous recombination hr, and factors. Adpribosylation by adpribosyltransferases arts has a wellestablished role in dna strand break repair by promoting enrichment of repair factors at damage sites through adpribose interaction domains. Repair of dna interstrand crosslinks sciencedirect. Dna interstrand crosslink repair during g1 involves nucleotide excision repair and dna polymerase zeta. Here, we exploit the simple eukaryote dictyostelium to uncover a role for adpribosylation in regulating dna interstrand crosslink repair and redundancy of this pathway with non. They can be formed by endogenous sources such as products of lipid metabolism and abasic sites, as well as by a number of antitumor agents such as nitrogen mustards, cisplatin and mitomycin c. Fanconi anemia, interstrand crosslink repair and cancer. Repair of icls involves multiple dna repair pathways.
Fanconi anemia is a human cancer predisposition syndrome caused by mutations in fanc genes. Dna interstrand crosslinks icls are extremely cytotoxic, but the. Replicationindependent repair of dna interstrand crosslinks. Journal dna interstrand crosslink repair during g1. A number of dna damaging agents broadly utilized in cancer treatment induce dna interstrand crosslinks icls 1114. An icl, however, constitutes an absolute block to dna. Dna interstrand crosslink repair in mammalian cells. Recent studies have revealed the mechanisms and the.
The preferential damage of mtdna and the absence of crosslink repair further suggests that mtdna may be a biologically important target for psoralen. Agents that induce icls were one of the earliest, and are. Fork reversal requires replicative cmg helicase unloading. Intrastrand crosslinks can be readily removed by the nucleotide excision repair ner mechanism. They show that ctip is tethered to damaged chromatin by.
Icls physically block cellular processes that require the unwinding of the dna molecule, such as replication, recombination, and transcription. Snm1a is involved in the repair of icls and disruption of snm1a leads to. We show that a functionally uncharacterized protein, hsf2bp, is involved in a novel, direct and highly evolutionarily conserved interaction with brca2. Although hsf2bp was previously described as testisspecific, we find it is. To investigate the possibility of measuring the genespecific dna damage after therapeutic exposure to nitrogen mustards and to examine its relationship with the clinical response. Fa is characterized by genomic instability and cellular sensitivity to dna interstrand cross linking agents. Hsf2bp negatively regulates homologous recombination in.
These adducts interfere with cellular metabolism, such as dna replication and transcription, triggering cell. Dna interstrand crosslinks icls are extremely cytotoxic lesions that are mainly repaired in a replicationcoupled manner. Dna interstrand crosslink repair and cancer andrew j. The role of brca2 in replicationcoupled dna interstrand crosslink repair in vitro.
Intrastrand crosslinks can be readily removed by the nucleotide excision repair ner mechanism 1. West abstract interstrand crosslinks icls are highly toxic dna lesions that prevent transcription and. In this work, fan1 dna crystal structures and biochemical data reveal that human fan1 cleaves dna successively at every third nucleotide. Here, we describe a cellfree system based on xenopus egg extracts that supports icl repair. Genetic deletion of ercc1 in the mouse causes dramatically accelerated aging. Parameswary a muniandy, jia liu, alokes majumdar, suting liu and michael m. Many cancer chemotherapeutic agents form dna interstrand crosslinks icls, extremely cytotoxic lesions that form covalent bonds between two opposing dna strands, blocking dna replication and transcription. Interstrand dna crosslinks icls are the link between watsoncrick strands of dnas with the covalent bond and prevent separation of dna strands. Dna interstrand crosslinks induced by psoralen are not repaired in mammalian mitochondria cancer research. Agents that cause dna interstrand crosslinks are widely used to treat cancer. Mechanism of rad51dependent dna interstrand crosslink repair. Dna interstrand crosslinks, with emphasis on repair, cell signaling, and therapeutic implications.
Interstrand crosslinks, which link the two complementary strands of dna together, comprise less than 5% of the total dna lesions but are highly cytotoxic and difficult to repair 8. Icls can be repaired by the fanconi anemia fa pathway and through faindependent processes involving the fan1 nuclease. Dna interstrand crosslink repair and cancer nature. Interstrand crosslinks icls are amongst the most cytotoxic dna lesions, covalently. In response to dna interstrand crosslinks icls, fancd2 coordinates several dna repair mechanisms in order to promote genome stability, yet its connection to homologous recombination hr is poorly understood.
The role of slx4 in dna interstrand crosslink repair hubrecht. Sequential use of three dna repair pathways to repair dna crosslinks. Dna interstrand crosslink repair during g1 involves nucleotide excision repair and dna polymerase f sovan sarkar1, adelina a davies2, helle d ulrich2 and peter j mchugh1, 1cancer research uk laboratories, weatherall institute of molecular medicine, university of. Crosslinking of dna an overview sciencedirect topics. Mechanism of replicationcoupled dna interstrand crosslink. The discovery of a safe mechanism that reverses such damage might open up. Dandrea, in the molecular basis of cancer fourth edition, 2015. Pmc free article this paper describes an important icl repair mechanism that is active in g1 phase of the cell cycle. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate dna interstrand crosslinks icls. A single icl can kill repair deficient bacteria and yeast, and about 40 icls can kill repair deficient mammalian cells. Interstrand dna crosslinks icls make up a particular subtype of dna lesions, and these lesions have an especially potent biological effect. This is the first report on the kinetics of genespecific monoadducts and dna interstrand crosslink formation and repair in a readily accessible tissue of cancer patients after. Pdf fanconi anemia proteins, dna interstrand crosslink. Research inhibition of carboplatininduced dna interstrand.
Request pdf on jan 22, 20, taraswi banerjee and others published fanconi anemia, interstrand crosslink repair and cancer find, read and cite all the research you need on researchgate. In genetics, crosslinking of dna occurs when various exogenous or endogenous agents react. We have recently shown enhanced repair of dna interstrand crosslinks in ovarian cancer cells from patients following treatment. Dna crosslinking damage and cancer a tale of friend and foe. Understanding the cellular response to dna damage induced by these agents is critical for more effective utilization of these compounds and for the. Human dna helicase helq participates in dna interstrand. The ability of cells to repair dna icls is a critical determinant of sensitivity, and recent clinical studies. The proteins involved in icl repair, in general, are required for resistance to icls and. Mechanism of dna interstrand crosslink processing by repair nuclease fan1 dna interstrand crosslinks icls are highly toxic lesions associated with cancer and. The kinetics of genespecific monoadducts and interstrand crosslink formation repair were measured in the p53 and n ras genes. Background the excision repair cross complementing ercc1 gene product plays a vital role in the nucleotide excision repair ner and dna interstrand crosslink repair pathways, which protect the genome from mutations and chromosomal aberrations, respectively. Translesion dna synthesis polymerases in dna interstrand.
Dna interstrand crosslinks icls are cytotoxic lesions that covalently link opposite strands of the dna helix and block dna unwinding. During dna replication of a plasmid containing a sitespecific icl, two replication forks converge on the crosslink. Dna interstrand crosslinkers, a chemically diverse group of compounds which also induce alkylation of bases and dna intrastrand crosslinks, are extensively utilized for cancer therapy. A central event in the activation of the fanconi anemia pathway is the monoubiquitylation of the fancifancd2 complex, but how this. In genetics, crosslinking of dna occurs when various exogenous or endogenous agents react with two nucleotides of dna, forming a covalent linkage between them. Novel crosslinking agents, and targeting strategies involving dna crosslinking agents, continue to be developed. Indirect evidence suggests that in metazoans, the principal. Despite the clinical success of crosslinking agents in antitumor. Genespecific formation and repair of dna monoadducts and. The tumor suppressor brca2 is essential for homologous recombination, replication fork stability and dna interstrand crosslink icl repair in vertebrates. Mechanisms of interstrand dna crosslink repair and human. Mechanism of replicationcoupled dna interstrand crosslink repair. Replication fork reversal during dna interstrand crosslink repair.
Icl repair that involves a reversed fork intermediate. Involvement of translesion synthesis dna polymerases in. Since many of these agents are of importance in genetic toxicology and cancer therapy, repair of interstrand crosslinks has been studied extensively in bacteria and in lower and higher eukaryotes. The role of brca2 in replicationcoupled dna interstrand. Here we discuss recent advances in our understanding of the. Seidman, dna interstrand crosslink repair in mammalian cells. Introduction dna interstrand crosslinks icls impede dna replication and transcription and are therefore extremely cytotoxic. Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrandcrosslink repair and low ercc1xpf expression. Only recently, however, have we begun to understand how cells repair these lesions. Reduced recruitment of 53bp1 during interstrand crosslink repair is. Mechanism of dna interstrand crosslink processing by. Mechanisms of interstrand dna crosslink repair and human disorders.
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