Review
HMGNs, DNA repair and cancer

https://doi.org/10.1016/j.bbagrm.2009.10.007Get rights and content

Abstract

DNA lesions threaten the integrity of the genome and are a major factor in cancer formation and progression. Eukaryotic DNA is organized in nucleosome-based higher order structures, which form the chromatin fiber. In recent years, considerable knowledge has been gained on the importance of chromatin dynamics for the cellular response to DNA damage and for the ability to repair DNA lesions. High Mobility Group N1 (HMGN1) protein is an emerging factor that is important for chromatin alterations in response to DNA damage originated from both ultra violet light (UV) and ionizing irradiation (IR). HMGN1 is a member in the HMGN family of chromatin architectural proteins. HMGNs bind directly to nucleosomes and modulate the structure of the chromatin fiber in a highly dynamic manner. This review focuses mainly on the roles of HMGN1 in the cellular response pathways to different types of DNA lesions and in transcriptional regulation of cancer-related genes. In addition, emerging roles for HMGN5 in cancer progression and for HMGN2 as a potential tool in cancer therapy will be discussed.

Introduction

High mobility group N (HMGN) family contains five chromatin architectural proteins, which are present in higher vertebrates. Of these proteins, HMGN1, 2 and 4 are expressed ubiquitously [1], [2], while HMGN3 and 5 are expressed in specific tissues [3], [4]. The HMGNs bind specifically to nucleosome core particles, which consist of 147 bp of DNA, wrapped around an octamer of core histones. The binding of HMGNs to nucleosomes has no sequence specificity and is mediated by their nucleosomal binding domain (NBD), which is the hallmark of this family of proteins. In living cells, HMGNs bind to nucleosomes temporally in a stop-and-go fashion and move continuously between binding sites. However, at any given moment most of the HMGNs are bound to chromatin, since their residence time on nucleosomes is longer than their transit time between nucleosomes. This highly dynamic binding to nucleosomes enables the HMGNs to regulate the chromatin structure both locally and globally [5], [6], [7], [8]. HMGNs regulation of the chromatin structure is achieved by their ability to affect the levels of various histone post-translational modifications [9], [10], [11], to compete with histone H1 for chromatin binding sites [12], [13] and to modulate the activity of chromatin remodeling factors [14]. Through these modes of action the HMGNs can induce de-compaction of the chromatin fiber.

The DNA packaged inside the chromatin fiber is constantly damaged by multiple agents. The insulting agents originate from internal metabolic processes and from external sources such as ultraviolet light (UV) and ionizing irradiation (IR). DNA lesions impose barriers for processes occurring on the DNA fiber, such as transcription and replication. DNA lesions also lead to genetic mutations and chromosomal aberrations, which are among the main causes of cancer development [15], [16], [17]. Throughout evolution several systems have evolved to identify the different types of lesions in the DNA, to adjust the cellular physiology to the insult and to repair the damage [17], [18]. In humans, approximately 150 genes are dedicated to responding and repairing damage in the DNA [19]. In recent years, additional proteins, which were previously seen only as organizers of chromatin in relation to transcription and replication, were shown to have important roles in the cellular ability to respond to various types of DNA lesions. Among those proteins is HMGN1. This review will describe the roles recently found for HMGN1 in DNA damage response as well as in cancer progression and the potential found for HMGN2 as a therapeutic tool for cancer remission.

Section snippets

Role of HMGN1 in the cellular response to UV light

UV light induces several types of DNA lesions of which the cyclobutane pyrimidine dimers (CPD) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4)PPs] are the most abundant [17], [18]. These lesions are repaired by the nucleotide excision repair (NER) pathway, which consists of two sub-pathways with different substrate specificity; global genome NER (GG-NER) and transcription-coupled repair (TCR). Both sub-pathways consist of ordered multi-step processes, which differ in the early steps, when

Role of HMGN1 in the cellular response to IR

Exposure of living organisms to IR leads to multiple types of DNA lesions including the double-stranded breaks (DSB), which are a dangerous insult for the stability of the genome. Formation of DSB in the genome leads to activation of a tightly regulated cascade of events termed DNA damage response (DDR), which controls the cellular response to the damage. In the DDR, the ternary protein complex MRN is the first recruit to the damage site. It facilitates the recruitment and activation of the

Role of HMGN1 in cancer progression

Cancer progression is thought to be dependent on the accumulation of mutations that change the transcriptional profile of the cell to support its escape from the tight regulation of cell cycle progression [51]. Improper responses to different types of DNA lesions that were detected in Hmgn1/ cells and mice may lead to accumulation of mutations in the genome, which then accelerates the progression of the disease. In addition to the global effects of HMGN1 in the cellular response to DNA

Perspective

HMGNs are chromatin architectural proteins which until lately were considered to be transcription co-regulators. However, in recent years their role in DNA repair and cancer progression has been established primarily by using HMGN1 knock-out mice [24], [44], [45]. These studies suggest that the archetype of the HMGNs family, HMGN1, has characteristics of a tumor suppressor gene.

HMGNs act inside the cell in a network of chromatin architectural proteins that compete with histone H1 for nucleosome

Acknowledgments

This study was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. I would like to thank M. Bustin (NCI), the NIH Fellows Editorial Board, R. Artzi-Gerlitz and V. Walker (NIH library) for constructive comments on the manuscript.

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