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的替代DNA结构的参与引起了人们的关注。一种类型的替代结构，十字形，已被证明在体外形成于包含回文的DNA序列。虽然强有力的证据因果关系牵连长回文DNA序列与人类遗传的相互易位，回文是否有助于易位在细胞以外的生殖细胞尚未得到证实。这种可能性在T和B淋巴细胞的情况下尤其相关，在这些细胞中，在分化过程中对精确的DNA代谢有额外的要求，并且尽管易位是淋巴系统肿瘤的显著特征，但潜在的错误仅被部分地确定。本研究的目的是测试的概念，（长）DNA回文可以煽动前/前B细胞易位。将研究小鼠前B细胞系（由Abelson鼠白血病病毒转化）和人前B细胞系Nalm 6中回文和易位之间的关系。将采用最近开发的在全基因组水平上表征易位的方法。这些研究可能会建立一个新的类别的内源性产生的DNA损伤的意义，在肿瘤的发生和其他病理学在淋巴系统和超越。 公共卫生相关性：作用于DNA以复制、转录、重组或修饰分子的酶都识别特定的结构。某些DNA序列具有呈现局部异常构象的趋势，并且这些具有被DNA酶不适当地操纵的风险。本提案旨在分析具有形成分支“十字形”结构的倾向的特定DNA序列基序（没有中心间隔区的反向重复序列），以确定其在细胞中引发染色体易位的能力。

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.