**6. Acknowledgment**

The research was supported by National Institutes of Health grant GM073837. The author is grateful for help during manuscript preparation to Mikhail Ryzhikov and Ekaterina Los. Significant portion of RecF studies were performed by graduate student Nodar Makharashivili.

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**23** 

Kaoru Sugasawa

*Kobe University* 

*Japan* 

**DNA Damage Recognition for Mammalian** 

*Biosignal Research Center, Organization of Advanced Science and Technology* 

As a blueprint for genetic information, the structural and functional integrity of DNA must be maintained during cell division and gamete formation. However, this fundamental principle is threatened continuously by the vulnerability of DNA itself and/or by assaults from endogenously produced agents, such as reactive oxygen species and other metabolites, as well as various environmental agents including ultraviolet light (UV), ionizing radiation and chemical compounds (Friedberg et al., 2006). Among the DNA components, bases in particular are frequently the targets for such insults. Because DNA replication and transcription rely on the formation of specific base pairs, even a subtle change in the base structures can compromise faithful propagation and the expression of genetic information. For instance, replicative DNA polymerases, which exhibit very high intrinsic fidelity, are often blocked at sites where template bases are modified, which can lead to replication fork collapse and consequent chromosomal aberrations and/or cell death. This problem is overcome, at least partly, by translesion DNA synthesis, which is an error-prone process (Friedberg et al., 2005). To minimize the risk of mutagenesis, it is crucial for growing cells to detect and to remove damaged bases as much as possible before replication forks collide

Nucleotide excision repair (NER) is a major DNA repair pathway that can eliminate an extremely broad spectrum of base damage. The NER substrates include dipyrimidinic UV photolesions, such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PPs), intrastrand crosslinks caused by bifunctional alkylating agents (e.g., cisplatin), and bulky base adducts induced by numerous chemical carcinogens (Gillet & Schärer, 2006). The common feature shared by all of these insults does not reside in their chemical structure, but rather in the accompanying distortions of the otherwise regular DNA helical structure. Two subpathways are associated with mammalian NER: global genome NER (GG-NER) and transcription-coupled NER (TC-NER). GG-NER is a general pathway that operates throughout the genome. It minimizes the collision of replication forks with damaged bases and, thereby, contributes to the maintenance of genome integrity (Gillet & Schärer, 2006). TC-NER is specialized to remove transcription-blocking lesions from the template DNA strands, which ensures rapid recovery of transcriptional activity and thus averts apoptosis (Hanawalt & Spivak, 2008). In humans, hereditary defects in NER are associated with several autosomal recessive disorders, including xeroderma

**1. Introduction** 

with them.

**Global Genome Nucleotide Excision Repair** 

