设万维读者为首页 万维读者网 -- 全球华人的精神家园 广告服务 联系我们 关于万维
 
首  页 新  闻 视  频 博  客 论  坛 分类广告 购  物
搜索>> 发表日志 控制面板 个人相册 给我留言
帮助 退出
莫扎特的长笛之博客  
生活本应如 --- 莫扎特的奏鸣曲般美好,来之不易,请珍惜之!  
https://blog.creaders.net/u/11674/ > 复制 > 收藏本页
网络日志正文
英文: 对永生的探索,修复DNA. Critical step in DNA repair 2017-03-14 20:45:08

Critical step in DNA repair, cellular aging pinpointed

  • Date:

  • March 23, 2017

  • Source: https://www.sciencedaily.com/releases/2017/03/170323150518.htm

  • Harvard Medical School

  • Summary:

  • The body's ability to repair DNA damage declines with age, which causes gradual cell demise, overall bodily degeneration and greater susceptibility to cancer. Now, research reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

FULL STORY


The body's ability to repair DNA damage declines with age, which causes gradual cell demise, overall bodily degeneration and greater susceptibility to cancer.

Credit: © rolffimages / Fotolia

DNA repair is essential for cell vitality, cell survival and cancer prevention, yet cells' ability to patch up damaged DNA declines with age for reasons not fully understood.

Now, research led by scientists at Harvard Medical School reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The findings, published March 24 in Science, offer a critical insight into how and why the body's ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. NAD, identified a century ago, is already known for its role as a controller of cell-damaging oxidation.

Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure.

The scientists caution that the effects of many therapeutic substances are often profoundly different in mice and humans owing to critical differences in biology. However, if affirmed in further animal studies and in humans, the findings can help pave the way to therapies that prevent DNA damage associated with aging and with cancer treatments that involve radiation exposure and some types of chemotherapy, which along with killing tumors can cause considerable DNA damage in healthy cells. Human trials with NMN are expected to begin within six months, the researchers said.

"Our results unveil a key mechanism in cellular degeneration and aging but beyond that they point to a therapeutic avenue to halt and reverse age-related and radiation-induced DNA damage," said senior author David Sinclair, professor in the Department of Genetics at HMS and professor at the University of New South Wales School of Medicine in Sydney, Australia.

A previous study led by Sinclair showed that NMN reversed muscle aging in mice.

A plot with many characters

The investigators started by looking at a cast of proteins and molecules suspected to play a part in the cellular aging process. Some of them were well-known characters, others more enigmatic figures.

The researchers already knew that NAD, which declines steadily with age, boosts the activity of the SIRT1 protein, which delays aging and extends life in yeast, flies and mice. Both SIRT1 and PARP1, a protein known to control DNA repair, consume NAD in their work.

Another protein DBC1, one of the most abundant proteins in humans and found across life forms from bacteria to plants and animals, was a far murkier presence. Because DBC1 was previously shown to inhibit vitality-boosting SIRT1, the researchers suspected DBC1 may also somehow interact with PARP1, given the similar roles PARP1 and SIRT1 play.

"We thought if there is a connection between SIRT1 and DBC1, on one hand, and between SIRT1 and PARP1 on the other, then maybe PARP1 and DBC1 were also engaged in some sort of intracellular game," said Jun Li, first author on the study and a research fellow in the Department of Genetics at HMS.

They were.

To get a better sense of the chemical relationship among the three proteins, the scientists measured the molecular markers of protein-to-protein interaction inside human kidney cells. DBC1 and PARP1 bound powerfully to each other. However, when NAD levels increased, that bond was disrupted. The more NAD present inside cells, the fewer molecular bonds PARP1 and DBC1 could form. When researchers inhibited NAD, the number of PARP1-DBC1 bonds went up. In other words, when NAD is plentiful, it prevents DBC1 from binding to PARP1 and meddling with its ability to mend damaged DNA.

What this suggests, the researchers said, is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and PARP1. The result: DNA breaks go unrepaired and, as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death and loss of organ function.

Averting mischief

Next, to understand how exactly NAD prevents DBC1 from binding to PARP1, the team homed in on a region of DBC1 known as NHD, a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team's experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair.

And, Sinclair added, since NHD is so common across species, the finding suggests that by binding to it, NAD may play a similar role averting harmful protein interactions across many species to control DNA repair and other cell survival processes.

To determine how the proteins interacted beyond the lab dish and in living organisms, the researchers treated young and old mice with the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can easily slip across it. Once inside the cell, NMN binds to another NMN molecule to form NAD.

As expected, old mice had lower levels of NAD in their livers, lower levels of PARP1 and a greater number of PARP1 with DBC1 stuck to their backs.

However, after receiving NMN with their drinking water for a week, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage.

In a final step, scientists exposed mice to DNA-damaging radiation. Cells of animals pre-treated with NMN showed lower levels of DNA damage. Such mice also didn't exhibit the typical radiation-induced aberrations in blood counts, such as altered white cell counts and changes in lymphocyte and hemoglobin levels. The protective effect was seen even in mice treated with NMN after radiation exposure.

Taken together, the results shed light on the mechanism behind cellular demise induced by DNA damage. They also suggest that restoring NAD levels by NMN treatment should be explored further as a possible therapy to avert the unwanted side effects of environmental radiation, as well as radiation exposure from cancer treatments.

In December 2016, a collaborative project between the Sinclair Lab and Liberty Biosecurity became a national winner in NASA's iTech competition for their concept of using NAD-boosting molecules as a potential treatment in cosmic radiation exposure during space missions.

Co-authors on the research included Michael Bonkowski, Basil Hubbard, Alvin Ling, Luis Rajman, Sebastian Moniot, Clemens Steegborn, Dapeng Zhang, L. Aravind, Bo Qin, Zhenkun Lou, and Vera Gorbunova.

The work was funded by the Glenn Foundation for Medical Research, the American Federation for Aging Research, Edward Schulak, grants from the National Institute on Aging and the National Institutes of Health, by the National Library of Medicine/NIH intramural program, the National Cancer Institute, and by Deutsche Forschungsgemeinschaft.

This research project was dedicated to David Sinclair's mother, Diana Sinclair, who bravely survived cancer for two decades.


Story Source:

Materials provided by Harvard Medical SchoolNote: Content may be edited for style and length.


Journal Reference:

  1. Jun Li, Michael S. Bonkowski, Sébastien Moniot, Dapeng Zhang, Basil P. Hubbard, Alvin J. Y. Ling, Luis A. Rajman, Bo Qin, Zhenkun Lou, Vera Gorbunova, L. Aravind, Clemens Steegborn, David A. Sinclair. A conserved NAD binding pocket that regulates protein-protein interactions during agingScience, 2017; 355 (6331): 1312 DOI: 10.1126/science.aad8242


浏览(880) (0) 评论(0)
发表评论
我的名片
MozartFlute
注册日期: 2016-10-02
访问总量: 179,212 次
点击查看我的个人资料
Calendar
我的公告栏
驰喻第2定律:
最新发布
· 英国钢琴事件之三: 非议和Mary
· 英国钢琴事件评论之二
· 英国钢琴事件之评论
· 随笔与非议6: AI写剧本;国会TIC
· 随笔与非议5.1: 乌克兰波兰对比
· 随笔与非议5: 乌克兰、波兰、与
· 随笔与非议4: 有关法轮功的两个
友好链接
· 润涛阎:润涛阎的博客
· 阿妞不牛:阿妞不牛的博客
· 伊萍:伊萍的多彩世界
· 高伐林:老高的博客
· 老冬儿:老冬儿的博客
· 格致夫:格致夫的博客
· 芦笛:芦笛的博客
分类目录
【电子技术和计算机】
【汽车知识】
【美食天地】
· [转帖]天气变冷了,适宜进补,试
【文摘转贴】
· 转贴:致全体中国知识分子的一封
· 转帖,冯韧:加拿大大选,不投票
· 川普对号入座? 世界是属于精神
· 转贴:美国贫富悬殊,社会治安恶
· 英文: CNN, 美国发射59颗导弹,
· 转大中报 碧海: 为何川普政府高
· 转载,藿香子: 从奥巴马医改看
· “科学美国人”中文版: 遗传学研究
· ENEWSTREE:川普反非法移民只是表
· FW: 逸草, 反谣言:穆斯林用高生
【物理学与宇宙精神】
· 人类有救了, 我们还可以多活10
· FW:霍金:不在一千年内逃离地球
【美好生活】
· 随笔与非议6: AI写剧本;国会TIC
· 追忆秋萍; 副标题: 盛赞加拿大
· 中篇小说连载:谈自由意志, 看
· [转帖]一个披着资本主义外衣的真
· 莫笛短篇: 一封私人信件, 我们
· 莫笛小说: 朋友池鱼的笔记, 琐事
· 英文: 对永生的探索,修复DNA. C
· 再评,川普的虚伪和无耻,他正在
· 转载: 于娟生命日记——《活着就
· 海密:克拉克瓷器简介
【古典音乐】
· 转贴:音乐、艺术、美学、哲学、
· 转贴:音乐、艺术、美学、哲学、
· FW: 莫扎特 の 萨尔茨堡的一天 |
· 转贴:莫扎特---一万年才出现一
· 文摘:如何欣赏莫扎特的音乐?
· 不要为了现实而忘记了永恒。介绍
【政治评论,正义与自由】
· 英国钢琴事件之三: 非议和Mary
· 英国钢琴事件评论之二
· 英国钢琴事件之评论
· 随笔与非议5.1: 乌克兰波兰对比
· 随笔与非议5: 乌克兰、波兰、与
· 随笔与非议4: 有关法轮功的两个
· 川普被抓?续
· 川普被FBI抓获?
· 随笔与理性争论3: 可能的对美战
· 随笔和理性争议2: 小舅走了,新
存档目录
2024-01-27 - 2024-01-28
2023-03-13 - 2023-03-25
2020-04-13 - 2020-04-21
2020-03-17 - 2020-03-17
2019-10-17 - 2019-10-17
2019-08-05 - 2019-08-05
2019-06-03 - 2019-06-03
2019-02-05 - 2019-02-05
2019-01-13 - 2019-01-13
2018-11-02 - 2018-11-04
2018-10-16 - 2018-10-31
2018-02-15 - 2018-02-25
2018-01-07 - 2018-01-21
2017-10-28 - 2017-10-28
2017-07-03 - 2017-07-03
2017-04-07 - 2017-04-07
2017-03-02 - 2017-03-31
2017-02-08 - 2017-02-28
2017-01-01 - 2017-01-18
2016-12-05 - 2016-12-25
2016-11-01 - 2016-11-29
2016-10-10 - 2016-10-30
 
关于本站 | 广告服务 | 联系我们 | 招聘信息 | 网站导航 | 隐私保护
Copyright (C) 1998-2024. CyberMedia Network /Creaders.NET. All Rights Reserved.