Molecular view of a key protein could help make cancer cells more vulnerable to treatments

Authors: Xiaodong Zhang (Imperial College London) , Luke Yates (Imperial College London)
Co-authored by industrial partner: No

Type: Diamond Annual Review Highlight

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 19865

Abstract: Damage to DNA needs to be repaired quickly, or it can result in defects that eventually cause cancer and ageing, particularly when a cell is replicating. Fortunately, our cells have evolved sophisticated pathways to counter the damage. One key process in the cell is the ‘DNA damage response’, where signalling factors are recruited that coordinate cell cycle progression with DNA repair. In humans, ATR is a key protein involved in the start of the repair process. A team of scientists at Imperial College London and Washington University School of Medicine in St. Louis used high-resolution cryo-electron microscopy (cryo-EM) structures to identify how ATR kick-starts the DNA repair process. ATR is sometimes mutated in cancer cells and is a validated drug target for cancer treatment. It and similar proteins are normally turned off (autoinhibited). They are activated when damage is detected. One key question is how ATR is maintained in an auto-inhibited state and how it is activated. The Mec1 yeast protein is essentially the same as human ATR. Using data collected at the Electron Bio-Imaging Centre (eBIC) at Diamond Light Source, the team obtained high-resolution structures of Mec1, in complex with its integral binding partner, Ddc2. In combination with biochemistry and genetics, these structures explain how this protein maintains an inhibited (off) state and the key steps required for its activation. These results allowed the researchers to propose a molecular mechanism for activation. This information helps to rationalise cancer mutations and provides a molecular framework for novel rational drug design of anticancer treatments.

Journal Keywords: Mec1/ATR; DNA damage response; Checkpoint control; Enzyme kinetics; Serine/threonine protein kinase; Cryo-EM structures; Activation mechanism

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond , Krios III-Titan Krios III at Diamond

Added On: 12/11/2021 11:44

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Genetics Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)