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Sunday, July 31, 2022

Junk DNA causes cancer

This is a story about misleading press releases. The spread of misinformation by press offices is a serious issue that needs to be addressed.

The Institute of Cancer Research in London (UK) published a press release on July 19, 2022 with the provocative title: ‘Junk’ DNA could lead to cancer by stopping copying of DNA. The first three sentences tell most of the story.

Scientists have found that non-coding ‘junk’ DNA, far from being harmless and inert, could potentially contribute to the development of cancer.

Their study has shown how non-coding DNA can get in the way of the replication and repair of our genome, potentially allowing mutations to accumulate.

It has been previously found that non-coding or repetitive patterns of DNA – which make up around half of our genome – could disrupt the replication of the genome.

Nobody ever said that junk DNA was "inert and harmless;" in fact it is assumed to be slightly deleterious and only gets fixed because it is invisible to natural selection in small populations (Nearly Neutral Theory). And no intelligent scientist equates noncoding DNA and junk DNA, even by implication. But in any case, this article isn't about all junk DNA, it's about certain small stretches of repetitive DNA that interfere with replication so that the resulting mutations have to be fixed by repair mechanisms. The most likely sequences to interfere with replication are repeats of CG or (CG)n repeats. As the authors point out in the discussion, these repeats are "extremely rare" in all genomes, including the human genome, suggesting that they are under negative selection.

Other, more common, repeats also show detectable in vitro interference with replisomes at replication forks. The errors introduced by replication stalling can be repaired but some of them will escape repair causing mutations. It's not clear to me why mutations in junk DNA are a problem. That's not explained in the paper.

Here's the paper.

Casas-Delucchi, C.S., Daza-Martin, M., Williams, S.L. et al. (2022) Mechchanism of replication stalling and recovery within repetitive DNA. Nat Commun 13:3953 [doi: 10.1038/s41467-022-31657-x]

Accurate chromosomal DNA replication is essential to maintain genomic stability. Genetic evidence suggests that certain repetitive sequences impair replication, yet the underlying mechanism is poorly defined. Replication could be directly inhibited by the DNA template or indirectly, for example by DNA-bound proteins. Here, we reconstitute replication of mono-, di- and trinucleotide repeats in vitro using eukaryotic replisomes assembled from purified proteins. We find that structure-prone repeats are sufficient to impair replication. Whilst template unwinding is unaffected, leading strand synthesis is inhibited, leading to fork uncoupling. Synthesis through hairpin-forming repeats is rescued by replisome-intrinsic mechanisms, whereas synthesis of quadruplex-forming repeats requires an extrinsic accessory helicase. DNA-induced fork stalling is mechanistically similar to that induced by leading strand DNA lesions, highlighting structure-prone repeats as an important potential source of replication stress. Thus, we propose that our understanding of the cellular response to replication stress may also be applied to DNA-induced replication stalling.

The word "junk" does not appear anywhere in the paper and the word "cancer" appears only once in the text where it refers to a "cancer-associated" mutation in yeast. This makes me wonder why the press release uses both of these words so prominently. Does anybody have any ideas?

Perhaps it has something to do with a quotation from Gideon Coster, who is described as the study leader. He says,

We wanted to understand why it seems more difficult for cells to copy repetitive DNA sequences than other parts of the genome. Our study suggests that so-called junk DNA is actually playing an important and potentially damaging role in cells, by blocking DNA replication and potentially opening the door to cancerous mutations.

I find it strange that he refers to "so-called junk DNA" in the press release but didn't mention it in the peer-reviewed paper. He also didn't emphasize cancerous mutations in the paper.

The press release contain another quotation, this time it's from Kristian Helin who is the Chief Executive of The Institute of Cancer Research. He says,

This study helps to unravel the puzzle of junk DNA – showing how these repetitive sequences can block DNA replication and repair. It’s possible that this mechanism could play a role in the development of cancer as a cause of genetic instability – especially as cancer cells start dividing more quickly and so place the process of DNA replication under more stress.

It's unclear to me how studying these mutation-inducing repeats could help "unravel the puzzle of junk DNA" but that's probably why I'm not the chief executive of a cancer research insitute. I'm so stupid that I didn't even known there WAS a "puzzle" of junk DNA to be unravelled!

It's time for scientists to speak out against press releases like this one. It misrepresents the results and their interpretation as published after undergoing peer review. Intead, the press release is used as a propaganda exercise to promote the personal views of the scientists—views that they couldn't publish. This is what happened with ENCODE and it's becoming more and more common. The fact that, in this case, the personal views of these scientists are flawed only makes the situation worse.

1 comment :

  1. When I started my Ph.D. program in the mid-nineties, one of my professors (half-jokingly) suggested that it was a good strategy to tie your grant applications to HIV research – by hook or by crook – since funding was relatively generous back then. Perhaps junk DNA denialism, which appears to be a hobbyhorse of Coster, is considered a winning strategy in the same vein. Of course studying "extremely rare" CG repeats is not going to address the 90% of the genome that is junk. They know it and so don't mention it in their paper. It would be interesting to see their grant applications.