Biomedical subjects

Kevin Lin

Publications and source records attributed to Kevin Lin.

4 recordsLinked to original sources

PubMed2025

Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation.

The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1LPHD stabilizes the ASH1LBAH fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1LPHD with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L.

Histones↗

PubMed2023

RNF4 and USP7 cooperate in ubiquitin-regulated steps of DNA replication.

DNA replication requires precise regulation achieved through post-translational modifications, including ubiquitination and SUMOylation. These modifications are linked by the SUMO-targeted E3 ubiquitin ligases (STUbLs). Ring finger protein 4 (RNF4), one of only two mammalian STUbLs, participates in double-strand break repair and resolving DNA-protein cross-links. However, its role in DNA replication has been poorly understood. Using CRISPR/Cas9 genetic screens, we discovered an unexpected dependency of RNF4 mutants on ubiquitin specific peptidase 7 (USP7) for survival in TP53-null retinal pigment epithelial cells. TP53-/-/RNF4-/-/USP7-/- triple knockout (TKO) cells displayed defects in DNA replication that cause genomic instability. These defects were exacerbated by the proteasome inhibitor bortezomib, which limited the nuclear ubiquitin pool. A shortage of free ubiquitin suppressed the ataxia telangiectasia and Rad3-related (ATR)-mediated checkpoint response, leading to increased cell death. In conclusion, RNF4 and USP7 work cooperatively to sustain a functional level of nuclear ubiquitin to maintain the integrity of the genome.

Animals↗

PubMed2002

Artifactual synchrony via capacitance coupling in multi-electrode recording from cat striate cortex.

Elucidation of neural connectivity patterns in the brain are thought to give us a mechanistic understanding of how the brain works. Functional connectivity is best studied by simultaneous recording of single-unit activity from many neurons. Accordingly, various types of multiple-microelectrode systems have been developed. We have studied long-range lateral interactions in cat striate cortex. To physiologically characterize interacting cells recorded simultaneously, we used two microelectrodes whose movements were controlled by two independently-movable microdrives. The tips of the two microelectrodes were separated by approximately 2 mm or more. During preliminary plotting of two receptive fields of cell pairs, we often noted the emergence of perfectly synchronous firing between two spike trains (amplitude ratio, about 20:1) registered with two microelectrodes. Synchronously firing, smaller spikes disappeared when larger spikes of the pair were lost to either substantial advancement of or placing an electrolytic lesion at the electrode registering the latter. The synchrony also disappeared when two microdrive systems were shielded individually. We concluded that the synchrony was attained through capacitance coupling between two microdrive systems. We proposed a few practical recommendations to avoid the contamination of cross correlograms with the false-positive, narrow peak at time zero due to the presence of reflected spike trains.

Action Potentials↗

PubMedDate not supplied

Early nodal response as a predictor for necessity of functional neck dissection after chemoradiation.

PURPOSE: Chemoradiation is increasingly becoming the standard of care for node-positive squamous cell cancer of the head and neck. Response to chemoradiation for clinically node-positive disease in the neck is often difficult to ascertain because clinical response may or may not be predictive of pathological response. This often leads to uncertainty about the necessity of a functional neck dissection after chemoradiation. In this study, we retrospectively analyzed a cohort of node-positive patients to examine pathological response as well as clinical outcome after chemoradiation with or without functional neck dissection. METHODS: Using the radiation oncology records from 1993 until 2003, a population of 420 patients with squamous cell cancer of the head and neck were identified. Of these, 34 patients were clinically node positive at the time of diagnosis and under went chemoradiation as their primary therapy. All patients received a concurrent platinum-based regimen. Median radiation dose to gross neck disease was 68.4 Gy (range: 50.4-73.8 Gy). RESULTS: Median follow-up time was 25 months (range: 4-88 months). Patients with a complete response (17/34, 50%) after receiving 50 Gy finished the full course of therapy but did not undergo functional neck dissection. Only one patient (1/17) in this observation group experienced relapse in the neck. Patients with a partial response who received 50 Gy (17/34) completed therapy and under went functional neck dissection, regardless of response at the end of therapy. Fifty percent (3/6) with positive pathology had a regional relapse in the neck, whereas only 1/11 patients with negative pathology relapsed in the neck. This result compared favorably with those who were observed after chemoradiation. CONCLUSIONS: Clinical response at 50 Gy can be an effective means of selecting patients for functional neck dissection. Patients with complete response at 50 Gy may be observed with a low regional recurrence rate. Those patients with a partial response should undergo adjuvant neck dissection.

Antineoplastic Combined Chemotherapy Protocols↗