Role of homologous recombination in carcinogenesis

doi:10.1016/S0014-4800(03)00010-8

Experimental and Molecular Pathology

Volume 74, Issue 2, April 2003, Pages 94-105

https://doi.org/10.1016/S0014-4800(03)00010-8 Get rights and content

Abstract

Cancer develops when cells no longer follow their normal pattern of controlled growth. In the absence or disregard of such regulation, resulting from changes in their genetic makeup, these errant cells acquire a growth advantage, expanding into precancerous clones. Over the past decade many studies have revealed the relevance of genomic mutation in this process, be it by misreplication, environmental damage, or a deficiency in repairing endogenous and exogenous damage. Here we discuss the possibility of homologous recombination as an errant DNA repair mechanism that can result in loss of heterozygosity or genetic rearrangements. Some of these genetic alterations may play a primary role in carcinogenesis, but they are more likely to be involved in secondary and subsequent steps of carcinogenesis by which recessive oncogenic mutations are revealed. Patients, whose cells display an increased frequency of recombination, also have an elevated frequency of cancer, further supporting the link between recombination and carcinogenesis.

Introduction

The genesis of a cancerous cell is a process of evolution and natural selection from a body of “normal” cells. It is now clear that the basis of this change is by genetic alteration, with the essential result being that a gene, or combination of genes, is altered to produce a cell that can bypass normal growth restrictions. Here we will present a body of evidence indicating that one of the important processes of genetic alteration in the generation of cancers is homologous recombination (HR). Evidence from our, and many other laboratories, has demonstrated that certain genetic deficiencies result in higher than normal levels of genomic instability including a higher frequency of HR. Patients with such genomic instability have a higher probability of developing cancers, as the instability allows a higher rate of genetic alteration. These alterations may result in either the direct mutation of an oncogenic gene or, more likely, it reveals an already mutated copy. In addition, we will present evidence that proliferating cells demonstrate the highest propensity for HR; in effect this predisposes proliferating cancer cells to an increased frequency of this form of genomic instability.

Section snippets

Models of carcinogenesis

Here we mention three commonly accepted models of carcinogenesis to highlight some of the processes that may involve a HR event. The simplest model for carcinogenesis is a one-step event. Most often, a mutation occurs in an oncogene that acts dominantly allowing oncogenesis. Examples of oncogenes include c-ABL1, H-RAS, c-MYC, c-ERBB, v-FOS, and c-JUN (Todd and Wong, 1999). Alternatively, the one-step model involves an inherited recessive defect that is exposed by the mutation of its functional

Homologous recombination in mammalian cells

Homologous recombination in mammalian cells is often considered to be less prevalent than an alternative recombination pathway, namely nonhomologous end-joining (NHEJ) (Kanaar et al., 1998). Thus, as a process of DNA repair and carcinogenesis, HR has often been overlooked (Lengauer et al., 1998). This idea is widely accepted, as it is well known that a large proportion of the mammalian genome contains repetitive DNA sequences (Mitchell, 1955b). Contrarily, recent studies have shown that

Homologous recombination in carcinogenesis

Homologous recombination may be playing a fundamental role in carcinogenesis. In the following sections we outline four situations where HR may have a fundamental part to play in the progression to cancer. First, we believe that HR can be a major mechanism in LOH, fulfilling the second step of the two-step model or a later event in the multistep model. Second, there are some cancer-prone diseases that have genetic instability as a phenotype, and some of these diseases also display an elevated

Conclusions

In conclusion, we have presented a body of evidence that HR can play a role in different stages of carcinogenesis. While HR may contribute to the initial steps of carcinogenesis, we believe that HR functions mostly as a secondary or subsequent step in tumor progression. If genomic rearrangements and deletion events were the cause of a portion of the cancers, it might also be expected that certain carcinogens would increase the frequency of genome rearrangements. This has in fact been elegantly

Acknowledgements

This work was supported by grants from the National Institute of Environmental Health Sciences (NIH RO1 No. ES09519) and the National Cancer Institute (NIH RO1 No. CA82473), as well as funding from the UCLA Center for Occupational and Environmental Health (to R.H.S.) and NIH RCDA Award No. F32GM19147 (to A.J.R.B.).

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Regular articleRole of homologous recombination in carcinogenesis

Abstract

Introduction

Section snippets

Models of carcinogenesis

Homologous recombination in mammalian cells

Homologous recombination in carcinogenesis

Conclusions

Acknowledgements

Mutat. Res.

J. Biol. Chem.

Mutat. Res.

Genomics

Mutat. Res.

Trends Biochem. Sci.

Cell

Mutat. Res.

Cell

Cell

Mutat. Res.

J. Biol. Chem.

Trends Biochem. Sci.

Cell

Cell

Mutat. Res.

Dermatologic Clinics

Curr. Opin. Cell Biol.

Trends Genet.

Mutat. Res.

Lance.

Trends Cell Biol.

Curr. Biol.

Cancer Genet. Cytogenet.

Trends Biochem. Sci.

Cell

J. Biol. Chem.

Am. J. Pathol.

Cell

J. Biol. Chem.

Curr. Opin. Genet. Dev.

Curr. Opin. Genet. Dev.

Clues to the pathogenesis of familial colorectal cancer

Science

Chemical carcinogenesistoo many rodent carcinogens

Proc Natl. Acad. Sci. USA

Too many rodent carcinogensmitogenesis increases mutagenesis [published erratum appears in Science 1990 Sept 28;249(4976):1487]

Science

Carcinogens induce intrachromosomal, recombination in human cells

Carcinogenesis

Involvement of p53 in X-ray induced intrachromosomal recombination in mice

Carcinogenesis

Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation

Nature

Increase of spontaneous intrachromosomal homologous recombination in mammalian cells expressing a mutant p53 protein

Oncogene

Susceptibility of proliferating cells to benzo[a]pyrene induced homologous recombination in mice

Carcinogenesis

Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice

Cancer Res.

Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing

EMBO J.

Interaction of p53 with the human Rad51 protein

Nucleic Acids Res.

Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention

Clin. Cancer Res.

Gross chromosomal rearrangements in Saccharomyces cerevisia replication and recombination defective mutants

Nature Genet.

Chromosome instability syndromes

Adv. Human Genet.

The role of genomic instability in human carcinogenesis

Anticancer Res.

Requirement of ATM-dependent phosphorylation of breal in the DNA damage response to double-strand breaks

Science

A deletion in chromosome 22 can cause DiGeorge syndrome

Human Genet.

BRCA1 and BRCA2 mutations among breast cancer patients from the Philippines

Int. J. Cancer

Regular article
Role of homologous recombination in carcinogenesis