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Larson, J. D.

Publications and source records attributed to Larson, J. D..

2 recordsLinked to original sources

Kinetochores grip microtubules with directionally asymmetric strength

For accurate mitosis, all chromosomes must achieve bi-orientation, with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends by directed transport or when side-attached microtubules shorten and bring their ends to the kinetochores. Mitotic accuracy depends on the selective release of erroneous attachments and proposed mechanisms have focused mainly on plus-end attachments. Whether erroneous side-attachments are distinguished from correct side-attachments is unknown. Here we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping six-fold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip correlates with changes in the axial arrangement of subcomplexes within the kinetochores, suggesting that internal architecture dictates attachment strength. We propose that the kinetochores directional grip promotes accuracy specifically during early mitosis, by stabilizing correct attachments even before both sisters have found plus ends.

biophysics↗

The landscape of extrachromosomal circular DNA in medulloblastoma

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate "enhancer rewiring" events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.

cancer biology↗