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Developmental biology - Genes

What keeps DNA From Falling Apart In Cell Division?

The AND-1 protein protects developing DNA strands from degrading...


DNA is often referred to as the "blueprint of life." In order for all living organisms to survive, it is vital a cell replicates by dividing into two cells. Replication underpins all genetic inheritance, and is supported by a whole range of biochemical interactions ensuring it occurs without error and at the right speed. Failure in replication can be catastrophic. So, understanding how all these specific mechanisms work is vitally important.

In 1998 FIRC (the Italian Foundation for Cancer Research) was created to fund the Molecular Oncology Institute and bring bench science to bedside applications. Now, researchers from Tokyo Metropolitan University (TMU) and the FIRC have succeeded in deleting the protein AND-1, to identify how key it is in DNA replication.
The AND-1/Ctf4 protein is found in a vast range of living organisms, from fungi to vertebrates. It is essential to some vertebrates for cell proliferation. But, it was not well understood in other organisms. Neither was it known why its loss affects cell proliferation.

A team led by Dana Branzei PhD from the Italian Institute of Molecular Oncology (IFOM) and professor Kouji Hirota from Tokyo Metropolitan University investigated the AND-1/Ctf4 protein by combining two elements, the DT40 cell line - a type of avian cell particularly suited to genetic engineering, with the auxin-based degron system for rapidly depleting proteins in nonplant cells.

Brazi and Hirota selectively depleted AND-1 protein from the DT40 cell line. This allowed them to successfully establish the and-1-aid cell line - which contains a modified version of AND-1 protein. The and-1-aid protein degrades in a few hours after adding auxin, a type of plant hormone. This new cell line gave the researchers the ability to analyze any consequences from loss of AND-1 and the role it plays in cell division.
Done correctly, DNA replication results in new double-stranded DNA helices. However, researchers observed that newly synthesized DNA has abnormally long single DNA strands located at a fork branching point. This observation led them to hypothesize this may be due to nuclease - a DNA cutting enzyme - disrupting DNA strands from being disassembled. When another compound called mirin (MRE11) was added to suppress nuclease, there was a reverse in the abnormal fork and recovery of cell division.

This explicitly demonstrates the key role played by AND-1 in preventing newly forming DNA cleavage activated by nuclease during replication. Continued analysis revealed a specific part of the protein called WD40 repeats is responsible for preventing damage accumulation to the DNA strand. The study has been published online in the journal Nature Communications.

This successful combination of cutting-edge techniques allows for new cells to be developed within a single month. An exciting prospect for the study of gene processes otherwise difficult to target.

Abstract
AND-1/Ctf4 bridges the CMG helicase and DNA polymerase alpha, facilitating replication. Using an inducible degron system in avian cells, we find that AND-1 depletion is incompatible with proliferation, owing to cells accumulating in G2 with activated DNA damage checkpoint. Replication without AND-1 causes fork speed slow-down and accumulation of long single-stranded DNA (ssDNA) gaps at the replication fork junction, with these regions being converted to DNA double strand breaks (DSBs) in G2. Strikingly, resected forks and DNA damage accumulation in G2, but not fork slow-down, are reverted by treatment with mirin, an MRE11 nuclease inhibitor. Domain analysis of AND-1 further revealed that the HMG box is important for fast replication but not for proliferation, whereas conversely, the WD40 domain prevents fork resection and subsequent DSB-associated lethality. Thus, our findings uncover a fork protection function of AND-1/Ctf4 manifested via the WD40 domain that is essential for proliferation and averts genome instability.

Authors
Takuya Abe, Ryotaro Kawasumi, Michele Giannattasio, Sabrina Dusi, Yui Yoshimoto, Keiji Miyata, Koyuki Umemura, Kouji Hirota and Dana Branzei.


Acknowledgements
This work was supported by the Italian Association for Cancer Research (IG 14171 and IG 18976), the European Research Council (Starting Grant 242928 and Consolidator Grant 682190) grants and a JSPS KAKENHI (JP16H02957).

The authors thank the Imaging facility at IFOM, the Electron Microscopy Technology Development Unit (TDU) at IFOM, H. Arakawa for reagents and K. Hanada for the PFGE protocol, M. Seki, A. Yoshimura and Y. Hosono for Tipin and Claspin cell lines, Branzei lab members for discussions. This work was supported by the Italian Association for Cancer Research (IG 14171 and IG 18976), and European Research Council (Starting Grant 242928 and Consolidator Grant 682190) grants to D.B. and KAKENHI JSPS (JP 16H02957) to K.H.


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Oct 2, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Nuclease as a DNA cutting enzyme, disrupts DNA strands from disassembly. When the compound mirin (MRE11) was added to suppress nuclease, reversal of abnormal fork formation was recovered allowing cell division to proceed normally. Image: Dana Brazi/Kouji Hirota.


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