SPDL1 (Spindly) Gene Review Notes

Gene Overview

SPDL1 (also known as CCDC99, Spindly, hSpindly) encodes Protein Spindly, a coiled-coil domain-containing protein that functions as a dynein adaptor at kinetochores during mitosis. UniProt: Q96EA4. 605 amino acids. Chromosome 5.

Key Publications and Findings

PMID:17576797 - Griffis et al. 2007, J Cell Biol

• Title: "Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore."
• VERIFIED: REAL - Published in J Cell Biol 177:1005-1015 (2007). Authors: Griffis ER, Stuurman N, Vale RD. HHMI/UCSF.
• This is the discovery paper for Spindly. Identified via RNAi screen in Drosophila S2 cells.
• Key findings: Spindly accumulates on unattached kinetochores; required for SAC silencing in Drosophila; dynein cannot target to kinetochores after Spindly depletion; human homologue identified with similar function.
• PMID:17576797

PMID:19468067 - Chan et al. 2009, J Cell Biol

• Title: "Mitotic control of kinetochore-associated dynein and spindle orientation by human Spindly."
• VERIFIED: REAL - Published in J Cell Biol 185:859-874 (2009). Authors: Chan YW, Fava LL, Uldschmid A, Schmitz MH, Gerlich DW, Nigg EA, Santamaria A.
• The primary characterization paper for human Spindly. This is the main reference for most experimental GO annotations.
• Key findings:
• hSpindly KT localization controlled by RZZ complex and Aurora B
• Depletion causes reduced inter-KT tension, unstable KT fibers, prometaphase delay, severe chromosome misalignment
• Depletion induces striking spindle rotation (rescued by co-depletion of dynein)
• In contrast to Drosophila, hSpindly depletion does NOT abolish removal of MAD2 and ZW10 from KTs
• Interacts with KNTC1 (Rod) and ZW10 (interactions appear weak/transient)
• Localizes to outer kinetochore (IDA), spindle pole (IDA), nucleus in interphase (IDA)
• PMID:19468067

PMID:25035494 - McKenney et al. 2014, Science

• Title: "Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes."
• VERIFIED: REAL - Published in Science 345:337-341 (2014). Authors: McKenney RJ, Huynh W, Tanenbaum ME, Bhabha G, Vale RD.
• Key finding: Spindly acts as an adapter protein linking the dynein motor complex to cargo; converts dynein from non-processive to highly processive motor in the presence of dynactin.
• This paper established the paradigm for dynein-dynactin activation by cargo adaptors (including BICD2, Spindly, etc.)

PMID:30258100 - Conte et al. 2018, Sci Rep

• Title: "USP45 and Spindly are part of the same complex implicated in cell migration."
• VERIFIED: REAL - Published in Sci Rep 8:14375 (2018). Authors: Conte C, Griffis ER, Hickson I, Perez-Oliva AB.
• Key findings:
• Spindly identified as a new interactor of USP45 by mass spectrometry
• Interaction depends on catalytic activity of USP45
• Spindly is monoubiquitinated; USP45 removes this monoubiquitin
• USP45 has preferential activity on K48 ubiquitin chains
• USP45 plays a role in cell migration similar to Spindly
• PMID:30258100

PMID:23382074 - Armour et al. 2013, Mol Cell Biol

• Title: "A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex."
• VERIFIED: REAL - Published in Mol Cell Biol 33:1487-1502 (2013).
• This paper is about SIRT1/USP22/SAGA complex. SPDL1 interaction with SIRT1 is likely a high-throughput finding from the interaction screen. The enzyme binding annotation (GO:0019899) from this paper is based on SPDL1 appearing in the SIRT1 interactome. The GOA annotation says the IPI is with Q96EB6 (SIRT1). This is from a large-scale interaction study.

PMID:25416956 - Rolland et al. 2014, Cell

• Title: "A proteome-scale map of the human interactome network."
• VERIFIED: REAL - Large-scale yeast two-hybrid study. SPDL1 interactions detected: CA8, RTP5, PPP1R18, DNAAF4, TRAF4, USP15.

PMID:25910212 - Sahni et al. 2015, Cell

• Title: "Widespread macromolecular interaction perturbations in human genetic disorders."
• VERIFIED: REAL - Follow-up to the interactome network study.

PMID:26871637 - Yang et al. 2016, Cell

• Title: "Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing."
• VERIFIED: REAL - Studies alternative splicing effects on protein interactions.

PMID:33961781 - Huttlin et al. 2021, Cell

• Title: "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome."
• VERIFIED: REAL - BioPlex 3.0 interactome study.

Additional key papers (not in current annotations):

PMID:20439434 - Gassmann et al. 2010, Genes Dev

• "Removal of Spindly from microtubule-attached kinetochores controls spindle checkpoint silencing in human cells."
• Identified conserved Spindly motif essential for dynein targeting to KT. Dynein-mediated removal of Spindly from KTs is the critical reaction in checkpoint silencing.

PMID:20427577 - Barisic et al. 2010, Mol Biol Cell

• "Spindly/CCDC99 is required for efficient chromosome congression and mitotic checkpoint regulation."
• Showed Spindly is a mitotic phosphoprotein, interacts with RZZ, and levels at KT are regulated by MT attachment and tension.

PMID:29915359 - Sacristan et al. 2018, Nat Cell Biol

• "Dynamic kinetochore size regulation promotes microtubule capture and chromosome biorientation in mitosis."
• Showed Spindly and RZZ drive kinetochore expansion (corona formation) in a dynein-independent manner. C-terminal farnesylation and MPS1 activity cause Spindly conformational changes promoting RZZ-Spindly oligomerization.

PMID:25825516 - Moudgil et al. 2015, J Cell Biol

• Showed hSpindly undergoes farnesylation at C-terminal cysteine, essential for KT localization and RZZ interaction.

BioReason Analysis Assessment

Verified claims in BioReason's deep research:

• Correct: IPR028593 (Protein Spindly, chordates) and IPR051149 (Spindly/BICDR Dynein Motor Adapter)
• Correct: Dynein adapter function at kinetochores
• Correct: Coiled-coil architecture (residues 2-442)
• Correct: Roles in chromosome alignment, spindle orientation, protein localization to KT

Questionable/unverified claims in BioReason:

• Claims about "BUB1B/BUB3" and "NDC80 complex" as direct Spindly receptors at the outer kinetochore: Not supported. Spindly binds via the RZZ complex (Rod/ZW10/Zwilch), not directly to BUB1B or NDC80. This is a significant error.
• Claims about "SKA1/2/3" and "CENP-F" as Spindly interactors: Not supported by literature. SKA complex and CENP-F are outer KT components but not established Spindly interactors.
• Claims about "HOX-D13" as a partner: No evidence for this. Likely hallucinated.
• Claims about "MKLN1 (BICDR)" association: BICDR1/BICDL1 (not MKLN1) is the related dynein adaptor. MKLN1 is muskelin, not the same protein. This is an error.
• The mention of GO:0098806 "Spindly-BICDR complex" needs verification - this GO term may not exist.
• Claims about "Golgi-directed transport" via Spindly: The cell migration role is documented but the Golgi mechanism is speculative.

Summary of BioReason accuracy:

The BioReason analysis gets the broad strokes correct (dynein adaptor, kinetochore localization, chromosome alignment, spindle orientation) but contains several specific errors about binding partners (BUB1B, NDC80, SKA, CENP-F, HOX-D13, MKLN1) that are not supported by the literature. The actual RZZ complex interaction is underemphasized.