Chromosome translocation in pre B cells: the role of an alternate DNA structure

描述（由申请人提供）：近年来，染色体易位和其他重排中DNA结构的变化引起了人们的关注。一种类型的替代结构，十字形，已被证明形成在DNA序列，包括一个回文在体外。虽然强有力的证据表明，长回文DNA序列与人类遗传的互惠易位有因果关系，但回文序列是否有助于生殖细胞以外的细胞易位尚未得到证实。这种可能性在T和B淋巴细胞的情况下特别相关，因为在分化过程中对精确的DNA代谢有额外的要求，而且，尽管易位是淋巴系统肿瘤的一个显著特征，但潜在的错误仅被部分定义。本研究的目的是测试（长）DNA回文可以在前/前B细胞中引发易位的概念。在小鼠前B细胞系（由Abelson小鼠白血病病毒转化）和人类前B细胞系Nalm6中，回文和易位之间的关系将被研究。一个最近发展的方法表征易位在全基因组水平将被采用。这些研究可能建立一种新的内源性DNA损伤类别，在淋巴系统及其他系统的肿瘤发生和其他病理中具有重要意义。

DESCRIPTION (provided by applicant): The involvement of alternative DNA structures in chromosome translocations and other rearrangements has gained attention in recent years. One type of alternative structure, a cruciform, has been demonstrated to form at DNA sequences that comprise a palindrome in vitro. While strong evidence causally implicates long palindromic DNA sequences with heritable reciprocal translocations in humans, whether palindromes contribute to translocation in cells other than germ cells has not been demonstrated. The possibility is particularly relevant in the case of T and B lymphoid cells where there are extra demands placed upon accurate DNA metabolism during differentiation, and where, although translocation is a marked feature in tumors of the lymphoid system, the underlying errors have been only partially defined. The purpose of the present study is to test the notion that (long) DNA palindromes can instigate translocation in pro/pre B cells. The relationship between palindromy and translocation in mouse pro B cell lines (transformed by Abelson murine leukemia virus), and in a human pre-B line, Nalm6, will be investigated. A recently developed method for characterizing translocation at a genome-wide level will be employed. These studies may establish a new category of endogenously generated DNA damage with significance in tumorigenesis and other pathologies in the lymphoid system and beyond. PUBLIC HEALTH RELEVANCE: Enzymes that work on DNA in order to replicate, transcribe, recombine or modify the molecule all recognize specific structures. Certain DNA sequences have a tendency to assume locally abnormal conformations, and these pose the risk of being improperly manipulated by DNA enzymes. The present proposal is aimed at analyzing a particular DNA sequence motif (an inverted repeat sequence with no central spacer) that has a tendency to form branched 'cruciform' structures, for its ability to instigate chromosomal translocations in cells.