一种用来防止细胞受到基因损伤的蛋白质最近被发现具有更重要的作用：保护这些细胞产生的后代。新研究证实，这种被称为ATM的蛋白不仅仅可以修复免疫系统DNA的双链结构破坏，并且在防止细胞将基因损伤传递给分裂后的子细胞过程中起着重要作用。
在年轻B淋巴细胞（一种负责对抗外来入侵者的免疫细胞）中，它们通过不断改变DNA来产生各种不同的表面受体，这保证了免疫细胞能精确识别不同的抗原，以上过程称为V(D)J。在发表于《细胞》（Cell）上的文章中，Rockefeller大学Michel Nussenzweig教授和国家癌症研究所的同事合作，发现当ATM不存在时，染色体在V(D)J中会受到破坏，并且细胞修复机制也不起作用。
正常的淋巴细胞含有多种蛋白，它们负责识别和修复染色体破损，一旦破损无法修复，它们将关闭细胞复制程序。较早研究显示，其它DNA修复蛋白在B淋巴细胞不同阶段起作用。
因此科学家开始着手研究V(D)J的作用。结果发现，ATM蛋白在B淋巴细胞中似乎有两个作用：它帮助修复DNA双链结构破损，并且它激活细胞检查机制以防止基因破坏的细胞分裂。
由于ATM蛋白变异在很多淋巴肿瘤——例如淋巴腺肿瘤和免疫系统的肿瘤等——中存在，因此这一结果意味着这些基因破坏可能导致染色体置换、基因物质的重排等最终导致癌症的因素。目前Michel小组正打算继续研究这些染色体置换发生的内部分子学机制。
原文：
Critical protein prevents DNA damage from persisting through generations
Disappearing act. Normal chromosomes are capped by complexes called telomeres (red), which act as buffers and lose a little bit of material every time the cell divides. When scientists looked at dividing immune system B cells that lacked the ATM protein, they saw that chromosome 12 (bottom left, green spots) was missing its telomeres, a defect commonly seen in lymphomas. Credit: Rockefeller University
A protein long known to be involved in protecting a cell from genetic damage has been found to play an even more important role in protecting the cell’s offspring. New research shows that the protein, known as ATM, is not only vital for helping repair double-stranded breaks in the DNA of immune cells, but is also part of a system that prevents genetic damage from being passed on when the cells divide.
Early in the life of B lymphocytes — the immune cells responsible for hunting down foreign invaders and labeling them for destruction — they rearrange their DNA to create various surface receptors that can accurately identify different intruders, a process called V(D)J recombination. Now, in a study published online in the journal Cell, Rockefeller University professor Michel Nussenzweig, in collaboration with his brother Andre Nussenzweig at the National Cancer Institute and their colleagues, shows that when the ATM protein is absent, chromosomal breaks created during V(D)J recombination go unrepaired, and checkpoints that normally prevent the damaged cell from replicating are lost.
Normal lymphocytes contain a number of restorative proteins, whose job it is to identify chromosomal damage and repair it or, if the damage is irreparable, prevent the cell from multiplying. Earlier research by Andre and Michel Nussenzweig had identified other DNA repair proteins that are important during different phases of a B lymphocyte’s life. It was during one of these studies, which examined genetic damage late in the life of a B cell, that they came across chromosomal breaks that could not be explained.
So the researchers began to look into the potential role of V(D)J recombination. “We were not expecting it to be responsible for the breaks we were seeing,” says Michel, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology. “Because for it to be responsible, the breaks would have had to happen early on; the cell would have to divide, mature, maintain the breaks and stay alive with broken chromosomes.” This, in fact, was precisely what they found.
The ATM protein appears to have two roles in a B cell: It helps repair the DNA double-strand breaks, and it activates the cell-cycle checkpoint that prevents genetically damaged cells from dividing. “ATM is required for a B cell to know that it has a broken chromosome. And if it doesn’t know that it seems to be able to keep on going,” says Michel, who’s also a Howard Hughes Medical Institute investigator.
Since the ATM protein is mutated in a number of lymphomas — cancers of the lymph and immune system — the new finding suggests to researchers that the lymphocytes could have been living with DNA damage for a long time, and that this damage likely plays a role in later chromosomal translocations, rearrangements of genetic materials that can lead to cancer.
Michel and his brother, who’ve been collaborators for more than a decade, intend to pursue the molecular mechanisms by which these chromosomal translocations occur. “I think it’s important to understand them,” he says, “because eventually we might be able to prevent these dangerous chromosome fusions.”
Citation: Cell: June 28, 2007
Source: Rockefeller University