[Frontiers in Bioscience 17, 1362-1388, January 1, 2012]

DNA repair mechanisms protect our genome from carcinogenesis

Maria Carolina Strano Moraes1, Januario Bispo Cabral Neto1,2, Carlos Frederico Martins Menck1

1Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1374, Sao Paulo, SP, Brazil, 2Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Xeroderma pigmentosum and other NER-related disorders: NER defects promote cancer prone and progeria syndromes
4. Ataxia-telangiectasia: starting point for understanding the DNA damage-response network
4.1. Which comes first: sensors or transducers?
5. The many facets of Fanconi anemia
5.1. ICLs: a huge challenge for DNA replication countered by a criss-cross pathway
5.2. FA/BRCA pathway and iPS cells technique: a hope in gene/cell therapy
6. Other genome instability syndromes related to DNA repair defects
6.1. MYH-associated polyposis (MAP) and Lynch syndromes
6.2. The Bloom, Werner and Rothmund-Thomson syndromes
6.3. Neurodegenerative and neuromuscular diseases
6.4. Atherosclerosis and the Metabolic syndrome
6.5. New target partners involved in DDR and more potential DNA repair related disorders
7. DNA repair and cancer chemotherapy
7.1. The PARP inhibitors
7.2. Targeting the FA/BRCA pathway for cancer therapy
8. Summary and perspectives
8.1. Unrepaired DNA damage: a shortcut towards cancer and aging
8.2. Targeting DNA damage responses for therapy
9. Acknowledgments
10. References

1. ABSTRACT

Human cells are constantly exposed to DNA damage. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum (XP), ataxia-telangiectasia (AT) and Fanconi anemia (FA). This review focuses on the historical discoveries related with these three diseases and describes their impact on the understanding of DNA repair mechanisms and the causes of human cancer. As deficiencies in DNA repair are also often related with progeria symptoms, unrepaired damage and aging are somehow related. Several other pathologies associated with DNA repair defects, genetic instability and increased cancer risk are also discussed. In fact, studies with cells from these many syndromes have helped in understanding important levels of protection against cancer and aging, although little help has actually been conferred to the patients in terms of therapy. Finally, the recent advances in combined basic and translational research on DNA repair and chemotherapy are presented.