Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair.

TRF2 (TERF2) binds to telomeric repeats and is critical for telomere integrity. Evidence suggests that it also localizes to non-telomeric DNA damage sites. However, this recruitment appears to be precarious and functionally controversial. We find that TRF2 recruitment to damage sites occurs by a two-step mechanism: the initial rapid recruitment (phase I), and stable and prolonged association with damage sites (phase II). Phase I is poly(ADP-ribose) polymerase (PARP)-dependent and requires the N-terminal basic domain. The phase II recruitment requires the C-terminal MYB/SANT domain and the iDDR region in the hinge domain, which is mediated by the MRE11 complex and is stimulated by TERT. PARP-dependent recruitment of intrinsically disordered proteins contributes to transient displacement of TRF2 that separates two phases. TRF2 binds to I-PpoI-induced DNA double-strand break sites, which is enhanced by the presence of complex damage and is dependent on PARP and the MRE11 complex. TRF2 depletion affects non-sister chromatid homologous recombination repair, but not homologous recombination between sister chromatids or non-homologous end-joining pathways. Our results demonstrate a unique recruitment mechanism and function of TRF2 at non-telomeric DNA damage sites.

A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death.

Glutamine is a conditionally essential amino acid for the growth and survival of rapidly proliferating cancer cells. Many cancers are addicted to glutamine, and as a result, targeting glutamine metabolism has been explored clinically as a therapeutic approach. Glutamine-catalyzing enzymes are highly expressed in primary and metastatic head and neck squamous cell carcinoma (HNSCC). However, the nature of the glutamine-associated pathways in this aggressive cancer type has not been elucidated. Here, we explored the therapeutic potential of a broad glutamine antagonist, DRP-104 (sirpiglenastat), in HNSCC tumors and aimed at shedding light on glutamine-dependent pathways in this disease. We observed a potent antitumoral effect of sirpiglenastat in HPV- and HPV + HNSCC xenografts. We conducted a whole-genome CRISPR screen and metabolomics analyses to identify mechanisms of sensitivity and resistance to glutamine metabolism blockade. These approaches revealed that glutamine metabolism blockade results in the rapid buildup of polyunsaturated fatty acids (PUFAs) via autophagy nutrient-sensing pathways. Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.

The Calm Before the Storm: A Pheochromocytoma Case Report.

Pheochromocytomas are rare tumors that arise from the sympathetic ganglia or adrenal medulla and secrete catecholamines that are known for the classic triad of headaches, profuse sweating, and paroxysmal hypertension. However, there have been instances of asymptomatic patients found to have a pheochromocytoma. Adrenal incidentalomas are accidentally discovered through radiologic imaging, and subsequent testing can confirm a pheochromocytoma. Here, we present a case of a 67-year-old female found to have an adrenal incidentaloma on kidney ultrasound (US) after presenting to the emergency room (ER) due to nausea. She had minimally elevated creatinine at the ER. At her follow-up with her primary care provider (PCP), a kidney US was ordered and showed a probable right suprarenal mass. Further abdominal computed tomography (CT) and abdominal magnetic resonance imaging (MRI) showed that the mass was indeed adrenal, but its etiology is considered indeterminant. Although asymptomatic, further biochemical tests showed elevated serum and urine metanephrines and normetanephrines. Together, these findings revealed that the adrenal mass was likely a silent pheochromocytoma. She underwent a successful right adrenalectomy with pathology confirming pheochromocytoma. This case adds to the literature on the existence of silent pheochromocytomas and highlights the importance of following up on any abnormal findings with a PCP. This patient, although asymptomatic from her pheochromocytoma, needed surgery to prevent possible pheochromocytoma crises, which could cause cardiovascular complications and even death.

Colonic Ganglioneuroma: A Combined Single-Institution Experience and Review of the Literature of Forty-Three Patients.

Ganglioneuromas (GNs) are rare, benign tumors composed of ganglion cells, nerve fibers, and glial cells. Three types of colonic GN lesions exist: polypoid GNs, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. Less than 100 cases of GN are documented in the literature. A 10-year retrospective search of the pathology database at our institution identified eight cases of colonic GNs. All cases were incidental. Seven of the eight cases presented with colonoscopy findings of small sessile polyps (ranging between 0.1 and 0.7 cm) treated with polypectomy, whereas one case showed a 4 cm partially circumferential and partially obstructing mass in the ascending colon, treated with right hemicolectomy. Almost two-thirds of the cases (5/8) demonstrated associated diverticulosis. All cases were positive for S100 protein and Synaptophysin via immunohistochemistry (IHC). No syndromic association was identified in any of the cases. We also conducted a comprehensive review using PubMed to identify cases of colonic GN reported in the literature. In total, 173 studies were retrieved, among which 36 articles met our inclusion criteria (35 patients and 3 cases on animals). We conclude that while most GNs are incidental and solitary small sessile lesions, many can be diffuse and associated with syndromes. In these cases, the tumor can result in bowel obstruction simulating adenocarcinoma.