From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Wed Sep 27 2000 - 18:14:18 MDT
I'm in the middle of genome analysis mode and get to spend
the day looking at Medline articles (you're all jealous
I know)... I must say though, when you really get into
the molecular machines that nature has devised, it is *really*
cool.
At any rate, once in a while you run across a paper that makes
you hit the side of your head and go "duuuuhhh". Here is one:
Oncogene 2000 Apr 13;19(16):1982-91, Gerbitz A, et al
"Retinoblastoma susceptibility protein, Rb, possesses multiple BRCT-Ws,
BRCA1 carboxyl-terminus-related W regions with DNA break-binding activity"
Abstract:
> The BRCT region, the carboxyl-terminus of BRCA1 (the breast cancer
> susceptibility gene 1 product), is ubiquitous in several proteins
> that participate in cell cycle checkpoints and DNA repair. We have
> previously shown that the BRCT regions of TopBP1 (DNA topoisomerase II
> binding protein 1) and BRCA1 bound DNA breaks. A BRCT-related region,
> BRCT-W1, in the retinoblastoma susceptibility gene product (Rb) also
> could bind DNA fragments, independently of DNA sequences. Five BRCT-W
> regions were found in the Rb family. All BRCT-Ws of Rb bound DNA fragments.
> Electron microscopy and treatment with an exonuclease showed that
> BRCT-Ws bound double-strand DNA breaks. Since some BRCTs are exceptional
> common relating elements in tumor suppression, our findings reveal novel
> aspects of the tumor suppression mechanism.
For those of you that don't speak genome, I'll translate. The bottom
line is that the BRCA1 gene the Rb (retinoblastoma) tumor suppressor
genes work by binding to DNA double strand breaks. BRCA1 and Rb are
found to be mutated in breast and retinal cancers respectively. DNA
double strand breaks are periodically caused by ionizing radation or
sometimes oxidative lesions). Presumably this either results in the
activation of repair mechanisms and/or triggering apoptosis (cell death).
I believe human cells have a tolerance level of several double strand
breaks before they decide to commit suicide. Presumably this is because
if the cells have too many double strand breaks it can't figure out which
ends are supposed to go back together. One example of what happens when
you put two chromosomes together improperly is Burkitt's lymphoma, when
the c-myc on chromosome 8 gets mis-joined into chromosomes 2, 14 or 22 into
various immunoglobulin genes that are normally "on" in white blood cells.
The mis-regulated c-myc causes the cells to divide out of control.
Mutations in the BRCA1, Rb or some of the other genes with BRCT regions
would allow the cells to accumulate double strand breaks and not
undergo apoptosis. In the face of normally operating rejoining
mechanisms this is going to turn the genome in that cell into
a huge jumbled mess. For those of you speaking computerese, imagine
what would happen if your virtual paging routines put the blocks
being paged out back into random locations in the paging file.
The human strategy contrasts with that of Deinococcus radiodurans that can
tolerate hundreds of double strand breaks and seems to be capable
of properly knitting its genome back together.
Robert
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