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A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell.
The MRN complex (MRE11-RAD50-NBS1) senses the break and activates ATM, which phosphorylates H2AX, CHK2 and p53. Pathway choice is set by resection: 53BP1-RIF1-Shieldin protect ends and favour classical NHEJ (Ku70/80, DNA-PKcs, Artemis, XRCC4-LIG4), dominant in G1 and used by radiation-damaged cells; BRCA1-CtIP promote resection in S/G2, RPA coats the single strand, and PALB2-BRCA2 load RAD51 to form a filament that invades the sister chromatid for accurate copying. Polymerase-theta-mediated end joining (TMEJ) is the backup that leaves microhomology-flanked deletions, the scar of HR deficiency. BRCA1/2, PALB2, RAD51C/D and ATM loss define HRD; such tumours cannot repair replication-associated breaks caused by PARP trapping, platinum crosslinks or topoisomerase poisons, and depend on POLQ and ATR. Reversion mutations, 53BP1/Shieldin loss (restoring resection in BRCA1-null cells), and fork protection restore HR under PARP-inhibitor pressure. DNA-PK inhibitors radiosensitise; ATM loss sensitises to ATR inhibition.
A torn page. The careful archivist (HR) fetches the twin copy from the shelf and transcribes it letter for letter; the hurried clerk (NHEJ) tapes the two halves together, losing a few words. Tumours missing the archivist survive on the clerk, so anything that adds more torn pages (PARP inhibitors, platinum, radiation) buries them.
It identifies a way that a good test produces a wrong answer, and it names the fix. Any plasma repair-gene result used to decide on a PARP inhibitor should be run with a paired blood control, or an older man may be treated for a marrow clone rather than for his prostate cancer.
It established plasma profiling as a routine alternative to tissue for the BRCA question in advanced prostate cancer, with a sensible rule attached: if plasma finds nothing actionable, go back to tissue. It also documents at scale both the extra resistance information plasma gives and the clonal haematopoiesis noise that comes with it.
It defines who a homologous recombination result should send to platinum: core-gene and biallelic carriers, germline or somatic, rather than any repair-gene variant.
It splits the alterations into two groups with different practical meanings. The repair defects are present at diagnosis at close to their castration-resistant prevalence, so testing early is worthwhile; AR, TP53 and RB1 changes accumulate later, so a diagnostic sample does not answer questions about the disease in front of you at relapse.
Germline and tumour testing for homologous recombination repair genes is now standard in metastatic prostate cancer, and olaparib is approved for BRCA-mutated disease after a hormonal agent.
The trial behind the second PARP inhibitor licensed in prostate cancer, and the evidence that a somatic BRCA alteration predicts response as well as an inherited one. Together with TOPARP-A it is why tumour as well as germline sequencing is recommended in metastatic disease.
Re-biopsy and re-sequencing at relapse can find repair defects and a higher mutation burden that the primary did not show, which matters for PARP inhibitor and immunotherapy eligibility in metastatic TNBC.
Germline testing for every pancreatic cancer patient, platinum first line for BRCA carriers, and olaparib maintenance for those who respond are all downstream of POLO.
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